EP1603901B1 - Tetrahydropyran compounds as tachykinin antagonists - Google Patents

Tetrahydropyran compounds as tachykinin antagonists Download PDF

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Publication number
EP1603901B1
EP1603901B1 EP04717163A EP04717163A EP1603901B1 EP 1603901 B1 EP1603901 B1 EP 1603901B1 EP 04717163 A EP04717163 A EP 04717163A EP 04717163 A EP04717163 A EP 04717163A EP 1603901 B1 EP1603901 B1 EP 1603901B1
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European Patent Office
Prior art keywords
phenyl
oxa
trifluoromethyl
bis
ethoxy
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EP04717163A
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German (de)
French (fr)
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EP1603901A1 (en
Inventor
Olivier Dirat
Jason Matthew Elliott
Ian Thomas Huscroft
Richard Alexander Jelley
Janusz Jozef Kulagowski
Piotr Antoni Raubo
Duncan Edward Shaw
Francine Sternfeld
Christopher John Swain
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Organon Pharma UK Ltd
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Merck Sharp and Dohme Ltd
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Priority claimed from GB0305280A external-priority patent/GB0305280D0/en
Priority claimed from GB0305281A external-priority patent/GB0305281D0/en
Priority claimed from GB0305283A external-priority patent/GB0305283D0/en
Priority claimed from GB0305282A external-priority patent/GB0305282D0/en
Priority claimed from GB0305279A external-priority patent/GB0305279D0/en
Priority claimed from GB0305822A external-priority patent/GB0305822D0/en
Priority claimed from GB0305823A external-priority patent/GB0305823D0/en
Application filed by Merck Sharp and Dohme Ltd filed Critical Merck Sharp and Dohme Ltd
Publication of EP1603901A1 publication Critical patent/EP1603901A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to a class of tetrahydropyran compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are useful as neurokinin 1 (NK-1) receptor antagonists.
  • NK-1 neurokinin 1
  • the present invention provides compounds of the formula (Ia): and pharmaceutically acceptable salts thereof wherein R 1 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, fluoroC 1-6 alkyl, fluoroC 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, NO 2 , CN, SR a , SOR a , SO 2 R a , CO 2 R a , CONR a R b , C 2-6 alkenyl, C 2-6 alkynyl or C 1-4 alkyl substituted by C 1-4 alkoxy, wherein R a and R b each independently represent hydrogen or C 1-4 alkyl; R 2 is hydrogen, halogen, C 1-6 alkyl, fluoroC 1-6 alkyl or C 1-6 alkoxy substituted by C 1-4 alkoxy; R 3 is hydrogen, halogen or fluoroC 1-6 alkyl; R 4 is hydrogen,
  • a 1 is fluorine or CF 3 ;
  • a 2 is fluorine or CF 3 ;
  • a 3 is hydrogen or fluorine;
  • a 4 is hydrogen, fluorine or bromine;
  • a 5 is methyl or hydroxymethyl; and
  • A, B, R 10 and R 11 are as defined in relation to formula (Ia).
  • One favoured group of compounds of the formula (Iab) are those of the formula (laba) and pharmaceutically acceptable salts thereof: wherein A 1 is hydrogen or fluorine, especially hydrogen; and A 2 is hydrogen or fluorine, especially fluorine.
  • alkyl or "alkoxy" as a group or part of a group means that the group is straight or branched.
  • suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
  • fluoroC 1-6 alkyl and “fluoroC 1-6 alkoxy” mean a C 1-6 alkyl or C 1-6 alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms.
  • fluoroC 1-4 alkyl means a C 1-4 alkyl group in which one or more (in particular I to 3) hydrogen atoms have been replaced by fluorine atoms.
  • fluoroC 1-3 alkyl and fluoroC 1-3 alkoxy groups for example, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , OCF 3 , OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 , and most especially CF 3 , OCF 3 and OCH 2 CF 3 .
  • cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • a suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
  • cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
  • alkenyl and “alkynyl” as a group or part of a group mean that the group is straight or branched.
  • suitable alkenyl groups include vinyl and allyl.
  • a suitable alkynyl group is propargyl.
  • halogen means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
  • the compounds of formula (Ia) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
  • the salts of the compounds of formula (Ia) will be non-toxic pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid.
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
  • suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • the present invention includes within its scope solvates of the compounds of formula (Ia) and salts thereof, for example, hydrates.
  • the compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • the preferred compounds of the formulae (Ia) and (Iaa) will have the stereochemistry of the 2-, 3-, 4- and 8-positions as shown in formulae (Iac) and (Iad)
  • the present invention further provides pharmaceutical compositions comprising one or more compounds of formula (Ia) in association with a pharmaceutically acceptable carrier or excipient.
  • compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
  • Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.
  • the present invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (Ia), which process comprises bringing a compound of formula (Ia) into association with a pharmaceutically acceptable carrier or excipient.
  • the compounds of formula (Ia) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity.
  • a comprehensive listing of clinical conditions, uses and methods of treatment for which the compounds of the present invention will be useful is disclosed in US patent No. 6,071,927 (see, in particular, column 10, line 14 to column 22, line 18).
  • the compounds of the present invention are useful in the treatment of a variety of disorders of the central nervous system.
  • disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; and anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders.
  • mood disorders such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder
  • anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias,
  • the compounds of the present invention are also particularly useful in the treatment of nociception and pain.
  • Diseases and conditions in which pain predominates include soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, migraine, episiotomy pain, and bums.
  • the compounds of the present invention are also particularly useful in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; in the treatment of inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritus and sunburn; and in the treatment of allergic disorders such as eczema and rhinitis.
  • respiratory diseases particularly those associated with excess mucus secretion
  • respiratory diseases such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm
  • inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rhe
  • the compounds of the present invention are also particularly useful in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as ulcerative colitis, Crohn's disease and irritable bowel syndrome.
  • GI gastrointestinal
  • disorders and diseases of the GI tract such as ulcerative colitis, Crohn's disease and irritable bowel syndrome.
  • the compounds of the present invention are also particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure.
  • emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure.
  • the compounds of formula (Ia) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy; by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting.
  • the excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.
  • a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • a compound of formula (Ia) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
  • treatment includes prophylactic use to prevent the occurrence or recurrence of any of the aforementioned conditions.
  • compounds of formula (Ia) may be prepared by the reaction of a compound of formula (IIa) wherein LG is a suitable leaving group such as an alkyl- or arylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); by reaction with an amine of formula (IIIa)
  • LG is a suitable leaving group such as an alkyl- or arylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine)
  • the reaction is preferably effected in the presence of a base, for example, an alkali metal carbonate, such as potassium carbonate, in a suitable organic solvent such as acetonitrile.
  • a base for example, an alkali metal carbonate, such as potassium carbonate
  • a suitable organic solvent such as acetonitrile.
  • the reaction ideally is performed at an elevated temperature, for example, between 40°C and 80°C, especially between 50°C and 70°C.
  • a particularly preferred compound of formula (IIa) is that wherein the group LG is mesylate, i.e. the group -OSO 2 CH 3 , which compound is prepared by reaction of the corresponding methanol with methanesulfonyl chloride in the presence of a base, such as triethylamine, and optionally a catalyst such as 4-N,N-dimethylaminopyridine.
  • a base such as triethylamine
  • a catalyst such as 4-N,N-dimethylaminopyridine.
  • the reaction is conveniently effected in a solvent such as a halogenated hydrocarbon, for example, dichloromethane.
  • compounds of formula (Iab) may be prepared by the reaction of a compound of formula (IIab) wherein LG is a suitable leaving group such as an alkyl- or arylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); by reaction with an amine of formula (IIIab)
  • LG is a suitable leaving group such as an alkyl- or arylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine)
  • a particularly preferred compound of formula (IIab) is that wherein the group LG is mesylate, i.e. the group -OSO 2 CH 3 , which compound is prepared by reaction of the corresponding methanol with methanesulfonyl chloride in the presence of a base, such as triethylamine, and optionally a catalyst such as 4-N,N-dimethylaminopyridine.
  • a base such as triethylamine
  • a catalyst such as 4-N,N-dimethylaminopyridine.
  • the reaction is conveniently effected in a solvent such as a halogenated hydrocarbon, for example, dichloromethane.
  • compounds of formula (Ia) may be prepared by the reaction of an amine of formula (IIIa) with a compound of formula (IVa) in the presence of a reducing agent, for example, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • a reducing agent for example, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • the reaction is conveniently effected in a suitable solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane, conveniently at about room temperature.
  • compounds of formula (Iab) may be prepared by the reaction of an amine of formula (IIIab) with a compound of formula (IVab) in the presence of a reducing agent, for example, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • a reducing agent for example, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • the reaction is conveniently effected in a suitable solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane, conveniently at about room temperature.
  • amines of formula (IIIa) may be prepared by other methods that would be readily apparent to one of ordinary skill in the art.
  • methods for the preparation of the spirocyclic amines are provided in the literature - see for instance, Bioorg. Med. Chem. Lett., 12 (2002) 1759-62 and International ( PCT) Patent Publication No. WO 01/87838 .
  • Compounds of formulae (IVa) and (IVab) may be prepared by conventional methods such as those described in International (PCT) Patent Publication No. WO 00/56727 , for instance, by the oxidation of a corresponding vinyl compound using oxygen and ozone.
  • the reaction is conveniently effected at a reduced temperature, such as at about -78°C, in the presence of an organic solvent such as an alcohol, for example, methanol, or a halogenated hydrocarbon, for example, dichloromethane, or a mixture thereof.
  • Treatment with dimethylsulfide liberates the desired aldehyde.
  • a strong oxidizing agent such as Dess-Martin periodinane
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973 ; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165 .
  • the compounds were found to be active with IC 50 at the NK 1 receptor of less than 100nM on said test method.
  • Lithium borohydride (1g, 45mmol) was added portionwise to a solution of 4-[2-( tert- butyldimethylsilyloxy)-1-hydroxyethyl]-piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester (Description 2; 11.2g, 24.1mmol) in tetrahydrofuran (75ml). The mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous sodium hydrogencarbonate solution, then partitioned between ethyl acetate and water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo to give the diol.
  • N-Methylmorpholine N-oxide (1g, 8.6mmol) and osmium tetroxide (2ml, 2.5% solution in tert -butanol) were added to a solution of (2 R ,3 R ,4 S )-2-[(1 R )-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-4-vinyl-tetrahydropyran (see Example 147 in WO 00/56727 ; 2g, 4.3mmol) in tetrahydrofuran (25ml) and water (10ml). The mixture was stirred at room temperature for one hour before sodium periodate (9g, 43mmol) was added.
  • Palladium hydroxide (20% on carbon, 20mg) was added as a slurry in ethanol to a solution of isomer A of the product of Description 9 (120mg, 0.25mmol) in ethanol (5ml).
  • the mixture was hydrogenated in a Parr apparatus (45 psi) for 30 minutes then filtered through Celite TM and washed with ethanol. The filtrate was concentrated in vacuo .
  • Solid sodium triacetoxyborohydride (107mg, 0.504mmol) was added to a stirred mixture of 2-[1- ⁇ (2 R ,3 R ,4 R )-2-[(1 R )-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde (Description 11; 121mg, 0.36mmol), (1 S ,4 R )-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4 R )-2-oxa-8-aza-spiro[4.5]dec-4-yl ester trifluoroacetate (Description 10; 130mg), triethylamine (0.1ml, 0.72mmol) and dichloromethane (3ml) at room temperature.
  • Methanesulfonyl chloride 50 ⁇ l, 0.63mmol was added to a mixture of [(2R,3R,4R)-2-[(1 R )-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methanol (Description 15; 235mg, 0.49mmol), triethylamine (133m, 0.97mmol), 4-N,N-dimethylaminopyridine (3mg, 0.02mmol) and dichloromethane (5ml) at 0°C.
  • Trimethyl(2-propynyloxy)silane (11.54m, 9.62g, 75mmol) was added dropwise to a stirred, cooled (-5°C) solution of ethyl magnesium bromide (1M in tetrahydrofuran, 75ml, 75mmol) in tetrahydrofuran (150ml), maintaining the internal temperature below 0°C.
  • the mixture was stirred at 0°C for 30 minutes, then at room temperature for 90 minutes.
  • the mixture was cooled to -5°C and 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (15.0g, 75mmol) was added slowly, maintaining the internal temperature below 0°C.
  • Tetrabutylammonium fluoride (1M in tetrahydrofuran, 80ml, 80mmol) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-trimethylsilyloxypropynyl)-1-piperidinecarboxylate (from step (i) above; 24.4g, 75mmol) in tetrahydrofuran (300ml) and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and water (200ml) was added.
  • n -Butyllithium (175ml, 0.28mol) was added dropwise over 45 minutes to a stirred, cooled (-70°C) solution of ethyl propiolate (32ml, 0.32mol) in tetrahydrofuran (250ml). The mixture was stirred at -70°C for 10 minutes, then a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (18.6g, 0.093 mol) in tetrahydrofuran (250ml) was added dropwise over 1 hour maintaining the internal temperature below -70°C.
  • 1,1-Dimethylethyl 1-oxa-2-oxo-8-azaspiro[4.5]decane-8-carboxylate (from step (iii) above; 5.0g, 19.58mmol) in tetrahydrofuran (150ml) was added dropwise over 45 min. to a stirred, cooled (0 °C) solution of methyl magnesium chloride (3M in tetrahydrofuran, 19.58m, 58.75mmol) in tetrahydrofuran (150ml). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into saturated aqueous ammonium chloride (200ml) and extracted with ethyl acetate (200ml).
  • Trifluoroacetic acid (10m) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxy-3-methylbut-1-yl)-1-piperidinecarboxylate (from step (iv) above; 3.9g, 13.57mmol) in dichloromethane (10ml) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH 2 Cl 2 /MeOH/NH 3 (Aq.) (90:10:1) to give the title compound (2.04g, 89%).
  • 3-Azetidinecarboxylic acid (4.0g, 39.6 mmol) was dissolved in 1N sodium hydroxide solution (40mL) and cooled to 0°C. Benzyl chloroformate (5.9mL, 41mmol) was added followed by further 1N sodium hydroxide solution (41mL) dropwise. The mixture was stirred vigorously for 16hrs then made acidic with 2N hydrochloric acid. This suspension was extracted with dichloromethane (2x100mL) and the extracts dried over MgSO 4 . Concentration yielded the title compound (9.3g, 39.6mmol, 100%).
  • Methyl 1-benzyloxycarbonyl-3-azetidinecarboxylate (from step (ii); 10.1g, 40mmol) was dissolved in tetrahydrofuran (120mL) and cooled to -78°C. A solution of lithium hexamethyldisilazide in tetrahydrofuran (1M, 58mL, 58mmol) was slowly added and the solution warmed to 0°C. After 15 mins. at this temperature, the resulting solution was cooled back to -78°C and tert -butyldimethylsilyloxy acetaldehyde was added and stirred to room temperature over 2hrs and quenched with water (200mL).
  • Benzyl 3-(1,2-dihydroxyethyl)-3-(hydroxymethyl)azetidine-1-carboxylate (from step (iii); 956mg, 3.4mmol) was dissolved in dichloromethane (150mL) and dibutyltin oxide (17mg) was added.
  • p-Toluenesulfonyl chloride (686mg, 3.6mmol) was added and the solution was cooled to 0°C.
  • Triethylamine (520 ⁇ L, 3.75mmol) was added dropwise and the solution was then allowed to stir at ambient temperature for 16hrs. Further triethylamine (260 ⁇ L, 1.9mmol) was added and after stirring for 2hrs, water (250mL) was added.
  • Benzyl 8-hydroxy-6-oxa-2-azaspiro[3.4]octane-2-carboxylate (from step (iv); 456mg, 1.7mmol) was dissolved in methanol (20mL) and 10% palladium on carbon (50mg) added. This suspension was hydrogenated at 20psi hydrogen for 2hrs then filtered. The filtrate was concentrated to give the title compound as a gum (214mg, 1.66mmol, 98% yield). m/z (ES + ) 130 (M+H).
  • the cooled mixture was diluted with water and extracted with ethyl acetate (2 x 50mL), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude yellow oil was purified on silica using 10-30% ethyl acetate in iso -hexane as eluant.
  • tert -Butyl 4-(3- ⁇ [ tert -butyl(dimethyl)silyl]oxy ⁇ propylidene)piperidine-1-carboxylate (from step (i) above; 0.9g) was dissolved in tetrahydrofuran (1mL); tetra-n-butylammonium fluoride (2.5mL, 1M in THF) was added and the mixture was stirred for 30 min until tlc analysis (50:50 ethyl acetate:hexane) showed that all starting material had reacted. This mixture was concentrated in vacuo.
  • the crude product was re-dissolved in tert-butanol (5mL) and water (1mL) and N-methylmorpholine N-oxide (322mg) was added and stirred until dissolved. Osmium tetroxide (0.15m, 2.5% in t-butanol) was added and the mixture was stirred for 12h. This mixture was concentrated in vacuo.
  • the crude product was purified by chromatography on silica using 1-6% methanol in dichloromethane as eluant to afford the product (480mg).
  • tert -Butyl 4-hydroxy-4- ⁇ 3-[(trimethylsilyl)oxy]prop-1-yn1-1-yl ⁇ piperidine-1-carboxylate (crude from step (i); 16.42g, ca. 50mmol) was stirred with tetrabutylammonium fluoride (90mmol) in tetrahydrofuran (170mL) at ambient temperature for 18h. Then the solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was separated and the aqueous was extracted with ethyl acetate.
  • reaction mixture was stirred at room temperature for 18h before it was partitioned between water and ethyl acetate.
  • the aqueous phase was extracted with ethyl acetate.
  • the combined organic phases were washed with saturated sodium sulfite solution, then brine and finally dried over magnesium sulfate, filtered and concentrated to give the crude mixture of products as a colourless oil.
  • the mixture was separated by flash chromatography on silica gel, eluting with a gradient solvent system of 50-100 % ethyl acetate in hexane, then 1-2 % methanol in ethyl acetate to furnish 1.03g of the title compound (48 %).
  • Triethylamine 140 ⁇ L, 1.0mmol was added to a suspension of 2-oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride (Description 8; 0.1g, 0.54mmol) in 1,2-dichloroethane (2ml). After 10 minutes, (2 R ,3 R ,4 R )-2-[(1 R )-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-carbaldehyde (see Example 43 in WO 00/56727 ; 0.24g, 0.54mmol) was added as a solution in 1,2-dichloroethane (3ml).
  • Methyl magnesium chloride (3.0M solution in tetrahydrofuran, 90 ⁇ l) was added to a solution of 8-[(2 R ,3 R ,4 R )-2-[(1 R )-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one (Example 15; 100mg, 0.16mmol) stirring in tetrahydrofuran (2ml) at room temperature. After 2 hours the reaction was quenched by addition of saturated ammonium chloride.
  • Ethynyl magnesium bromide (0.5M solution in tetrahydrofuran, 0.5mL) was added to a solution of 8-[(2 R ,3 R ,4 R )-2-[(1 R )-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one (Example 15) (100mg, 0.16mmol) stirring in tetrahydrofuran (2ml) at room temp. After 2 hours the reaction was quenched by addition of saturated ammonium chloride.
  • This product was prepared according to the procedure described in Example 2 using (2 R ,3 R ,4 R )-2-[(1 R )-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-carbaldehyde ( WO 0056727 ) and 4-hydroxy-1-oxa-8-azaspiro[4.5]decane (Description 20).
  • This product was prepared according to the procedure described in Example 6 using (2 R ,3 R ,4 R )-2-[(1 R )-1-(3, 5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde (Description 11) and 4-hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane (Description 21).

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Abstract

The present invention relates to compounds of formula (Ia) wherein A, B, n, m, R<SUP>1</SUP>, R<SUP>2</SUP>, R<SUP>3</SUP>, R<SUP>4</SUP>, R<SUP>5</SUP>, R<SUP>6</SUP>, R<SUP>7</SUP>, R<SUP>8</SUP>, R<SUP>9</SUP>, R<SUP>10 </SUP>and R<SUP>11 </SUP>are defined herein, and pharmaceutically acceptable salts thereof; the compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, emesis or postherpetic neuralgia.

Description

  • This invention relates to a class of tetrahydropyran compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are useful as neurokinin 1 (NK-1) receptor antagonists.
  • Published International patent applications WO 00/56727 , WO 00/56728 , WO 02/16343 and WO 02/16344 (all Merck Sharp and Dohme Limited) all disclose tetrahydropyran derivatives which are useful as tachykinin antagonists, especially as NK-1 receptor antagonists.
  • The present invention provides compounds of the formula (Ia):
    Figure imgb0001
     and pharmaceutically acceptable salts thereof
    wherein
    R1 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb each independently represent hydrogen or C1-4alkyl;
    R2 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
    R3 is hydrogen, halogen or fluoroC1-6alkyl;
    R4 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, hydroxy, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb are as previously defined;
    R5 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
    R6 represents hydrogen or a C1-4alkyl group optionally substituted by a hydroxy group;
    R7 represents hydrogen, C1-6alkyl, fluoroC1-6alkyl, hydroxy, C1-6alkoxy or hydroxyC1-6alkyl;
    R8 and R9 each independently represent hydrogen, halogen, C1-6alkyl, CH2ORc, oxo, CO2Ra or CONRaRb where Ra and Rb are as previously defined and Rc represents hydrogen, C1-6alkyl or phenyl;
    A represents an oxygen atom or a CH2 group;
    B represents an oxygen atom or a CH2 group, with the proviso that when A is an oxygen atom, B is a CH2 group, and when A is a CH2 group, B is an oxygen atom;
    n is 1 or 2;
    m is 1, 2 or 3, with the proviso that the sum total of m + n is 2, 3 or 4;
    R10 is hydrogen, halogen, hydroxy, C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, C2-6alkenyl or C2-6alkynyl;
    R11 is hydrogen, halogen, hydroxy or C1-4alkyl;
    or R10 and R11 may together represent an oxo (=O) group, with the proviso that the oxo group is not adjacent to the oxygen atom represented by either A or B;
    wherein one or both of R10 and R11 may replace one or both hydrogen atoms in the CH2 group represented by A or B.
  • One favoured group of compounds of the formula (Ia) are those of the formula (Iaa) and pharmaceutically acceptable salts thereof:
    Figure imgb0002
     wherein
    A1 is fluorine or CF3;
    A2 is fluorine or CF3;
    A3 is hydrogen or fluorine;
    A4 is hydrogen, fluorine or bromine;
    A5 is methyl or hydroxymethyl; and
    A, B, R10 and R11 are as defined in relation to formula (Ia).
  • Another favoured group of compounds of the formula (Ia) are those of the formula (Iab) and pharmaceutically acceptable salts thereof:
    Figure imgb0003
     wherein
    X represents CHOH or C=O;
    R1 is fluorine or trifluoromethyl;
    R2 is fluorine or trifluoromethyl;
    R3 is methyl or hydroxymethyl;
    R4 is hydrogen or fluorine; and
    R5 is hydrogen or fluorine;
    and pharmaceutically acceptable salts thereof.
  • One favoured group of compounds of the formula (Iab) are those of the formula (laba) and pharmaceutically acceptable salts thereof:
    Figure imgb0004
     wherein
    A1 is hydrogen or fluorine, especially hydrogen; and
    A2 is hydrogen or fluorine, especially fluorine.
  • When any variable occurs more than one time in formula (Ia) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
  • As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
  • As used herein, the terms "fluoroC1-6alkyl" and "fluoroC1-6alkoxy" mean a C1-6alkyl or C1-6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly, the term "fluoroC1-4alkyl" means a C1-4alkyl group in which one or more (in particular I to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroC1-3alkyl and fluoroC1-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3.
  • The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
  • Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
  • As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a group mean that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
  • When used herein the term "halogen" means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
  • Specific compounds within the scope of this invention include:
    • (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;
    • (4S)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;
    • (4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;
    • (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;
    • 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane;
    • 8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane;
    • 8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane;
    • 8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane;
    • 8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane;
    • 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane;
    • 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane;
    • 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane;
    • 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane;
    • 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one;
    • (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-4-methyl-8-aza-spiro[4.5]decan-4-ol;
    and pharmaceutically acceptable salts thereof.
  • Specific compounds within the scope of this invention also include:
    • (4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;
    • (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-4-ethynyl-8-aza-spiro[4.5]decan-4-ol;
    • (8S)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenyl)tetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol;
    • (8R)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol;
    • (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyltetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;
    • (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-4-ol;
    • (4R*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;
    • (4S*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;
    • (4R)-8-[((2R,3R,4R)-2- {(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane;
    • (4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)tetrahydro-2H-pyran-4-yl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane;
    • 8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-ol;
    • 8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-one;
    and pharmaceutically acceptable salts thereof.
  • In a further aspect of the present invention, the compounds of formula (Ia) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
  • For use in medicine, the salts of the compounds of formula (Ia) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • The present invention includes within its scope solvates of the compounds of formula (Ia) and salts thereof, for example, hydrates.
  • The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • The preferred compounds of the formulae (Ia) and (Iaa) will have the stereochemistry of the 2-, 3-, 4- and 8-positions as shown in formulae (Iac) and (Iad)
    Figure imgb0005
  • It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred classes of compound represented by formula (Iaa), formula (Iac) and formula (Iad).
  • The preferred compounds of the formulae (Iab) and (Iaba) will have the stereochemistry of the 2-, 3-, 4- and 8-positions as shown in formulae (Iabb) and (Iabc)
    Figure imgb0006
  • It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred classes of compound represented by formula (Iaba), formula (Iabb) and formula (Iabc).
  • The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (Ia) in association with a pharmaceutically acceptable carrier or excipient.
  • Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.
  • A more detailed description of pharmaceutical compositions that are suitable for the formulation of compounds of the present invention is disclosed in US patent No. 6,071,927 (see in particular, column 8, line 50 to column 10, line 4).
  • The present invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (Ia), which process comprises bringing a compound of formula (Ia) into association with a pharmaceutically acceptable carrier or excipient.
  • The compounds of formula (Ia) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity. A comprehensive listing of clinical conditions, uses and methods of treatment for which the compounds of the present invention will be useful is disclosed in US patent No. 6,071,927 (see, in particular, column 10, line 14 to column 22, line 18).
  • In particular, the compounds of the present invention are useful in the treatment of a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; and anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders.
  • The compounds of the present invention are also particularly useful in the treatment of nociception and pain. Diseases and conditions in which pain predominates, include soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, migraine, episiotomy pain, and bums.
  • The compounds of the present invention are also particularly useful in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; in the treatment of inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritus and sunburn; and in the treatment of allergic disorders such as eczema and rhinitis.
  • The compounds of the present invention are also particularly useful in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as ulcerative colitis, Crohn's disease and irritable bowel syndrome.
  • The compounds of the present invention are also particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (Ia) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy; by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting.
  • The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.
  • In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
  • For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • In the treatment of emesis, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • In the treatment of psychiatric disorders, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • It will be appreciated that the amount of a compound of formula (Ia) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
  • As used herein, the term "treatment" includes prophylactic use to prevent the occurrence or recurrence of any of the aforementioned conditions.
  • According to a general process (Aa), compounds of formula (Ia) may be prepared by the reaction of a compound of formula (IIa)
    Figure imgb0007
     wherein LG is a suitable leaving group such as an alkyl- or arylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); by reaction with an amine of formula (IIIa)
    Figure imgb0008
  • The reaction is preferably effected in the presence of a base, for example, an alkali metal carbonate, such as potassium carbonate, in a suitable organic solvent such as acetonitrile. The reaction ideally is performed at an elevated temperature, for example, between 40°C and 80°C, especially between 50°C and 70°C.
  • A particularly preferred compound of formula (IIa) is that wherein the group LG is mesylate, i.e. the group -OSO2CH3, which compound is prepared by reaction of the corresponding methanol with methanesulfonyl chloride in the presence of a base, such as triethylamine, and optionally a catalyst such as 4-N,N-dimethylaminopyridine. The reaction is conveniently effected in a solvent such as a halogenated hydrocarbon, for example, dichloromethane.
  • Using general process (Aa), compounds of formula (Iab) may be prepared by the reaction of a compound of formula (IIab)
    Figure imgb0009
     wherein LG is a suitable leaving group such as an alkyl- or arylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); by reaction with an amine of formula (IIIab)
    Figure imgb0010
  • A particularly preferred compound of formula (IIab) is that wherein the group LG is mesylate, i.e. the group -OSO2CH3, which compound is prepared by reaction of the corresponding methanol with methanesulfonyl chloride in the presence of a base, such as triethylamine, and optionally a catalyst such as 4-N,N-dimethylaminopyridine. The reaction is conveniently effected in a solvent such as a halogenated hydrocarbon, for example, dichloromethane.
  • According to another general process (Ba), compounds of formula (Ia) may be prepared by the reaction of an amine of formula (IIIa) with a compound of formula (IVa)
    Figure imgb0011
     in the presence of a reducing agent, for example, sodium triacetoxyborohydride or sodium cyanoborohydride. The reaction is conveniently effected in a suitable solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane, conveniently at about room temperature.
  • Further details of suitable procedures will be found in the accompanying Examples.
  • Using general process (Ba), compounds of formula (Iab) may be prepared by the reaction of an amine of formula (IIIab) with a compound of formula (IVab)
    Figure imgb0012
     in the presence of a reducing agent, for example, sodium triacetoxyborohydride or sodium cyanoborohydride. The reaction is conveniently effected in a suitable solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane, conveniently at about room temperature.
  • Further details of suitable procedures will be found in the accompanying Examples.
  • Compounds of formulae (IIa) and (IIab) may be prepared by conventional methods such as those described in International (PCT) Patent Publication No. WO 00/56727 .
  • Compounds of formula (IIIa), and compounds of formula (IIIab) wherein X is CHOH, may be prepared from a suitably substituted precursor piperidine compound, for instance, as shown in Scheme 1 (in which R is, for example, a C1-6alkyl group, such as an ethyl group, and P is an amino protecting group, such as a benzyloxycarbonyl group):
    Figure imgb0013
  • An alternative (asymmetric) synthesis of compounds of formula (IIIa), and compounds of formula (IIIab) wherein X is CHOH, is shown in Scheme 2:
    Figure imgb0014
  • A further alternative (asymmetric) synthesis of compounds of formula (IIIa), and compounds of formula (IIIab) wherein X is CHOH, is shown in Scheme 3:
    Figure imgb0015
  • It will be appreciated that numerous other routes will be readily apparent to one of ordinary skill in the art, the route of choice depending upon the particular spiro-amine that is desired. The methodology described herein may be adapted accordingly. Thus, for instance, in addition to the processes outlined in Schemes 1, 2 and 3 above, amines of formula (IIIa) may be prepared by other methods that would be readily apparent to one of ordinary skill in the art. For example, methods for the preparation of the spirocyclic amines are provided in the literature - see for instance, Bioorg. Med. Chem. Lett., 12 (2002) 1759-62 and International ( PCT) Patent Publication No. WO 01/87838 .
  • Compounds of formulae (IVa) and (IVab) may be prepared by conventional methods such as those described in International (PCT) Patent Publication No. WO 00/56727 , for instance, by the oxidation of a corresponding vinyl compound using oxygen and ozone. The reaction is conveniently effected at a reduced temperature, such as at about -78°C, in the presence of an organic solvent such as an alcohol, for example, methanol, or a halogenated hydrocarbon, for example, dichloromethane, or a mixture thereof. Treatment with dimethylsulfide liberates the desired aldehyde.
  • It will be appreciated that the general methodology described above may be adapted, using methods that are readily apparent to one of ordinary skill in the art, in order to prepare further compounds of the present invention. In particular, compounds of formula (Ia) may be interconverted into further compounds of formula (Ia) using conventional synthetic techniques such as N-alkylation or O-alkylation, oxidation or reduction.
  • Thus, for instance, a compound of formula (Ia) or (Iab) wherein X is CHOH may be converted into a corresponding compound of formula (Ia) or (Iab) respectively wherein X is C=O by reaction with a strong oxidizing agent, such as Dess-Martin periodinane, to afford the desired ketone.
  • Other general methods that may be adapted to the synthesis of the pyran acetal derivatives of the present invention are described in International (PCT) Patent Publication Nos. WO 00/56727 and WO 02/16344 .
  • During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165 . The compounds were found to be active with IC50 at the NK1 receptor of less than 100nM on said test method.
  • The following Examples serve to illustrate the preparation of compounds of the present invention:
    • DESCRIPTION 1 Piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester
  • A solution of benzyl chloroformate (95g, 0.56mol) in dichloromethane (200ml) was added dropwise to an ice-bath-cooled, stirred mixture of ethyl isonipecotate (87g, 0.55mol), sodium carbonate (60g, 0.57mol) and dichloromethane (200ml) over 70 minutes. The mixture was stirred at ambient temperature for 2.5 days and filtered though a pad of Celite™. The filtrate was concentrated in vacuo. The residue was partitioned between 2M aqueous hydrochloric acid and diethyl ether. Organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel (ethyl acetate/iso-hexane) to give the title product (152g, 94%).
    1H NMR(360 MHz, CDCl3): δ 7.41-7.27 (5H, m), 5.12 (2H, s), 4.22-3.99 (2H, m), 4.14 (2H, q, J 7.4Hz), 2.93 (2H, br t, J 11.6Hz), 2.45 (2H, m), 1.97-1.81 (2H, m), 1.74-1.56 (2H, m), 1.25 (3H, t, J 7.4Hz).
    • DESCRIPTION 2 4-[2-(tert-Butyldimethylsilyloxy)-1-hydroxyethyl]-piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester
  • A solution of piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester (Description 1; 10g, 34.4mmol) in tetrahydrofuran (100ml) was cooled to -78°C. Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran, 50ml, 50mmol) was added dropwise and the mixture stirred, allowing to warm to room temperature over 1.5 hours. The orange solution was re-cooled to -78°C and (tert-butyldimethylsilyloxy)acetaldehyde (10g, 57.3mmol) added. The mixture was allowed to warm to room temperature over 2.5 hours, then quenched with saturated aqueous ammonium chloride solution. The reaction mixture was partitioned between diethyl ether and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5 -15% diethyl ether/dichloromethane, to give the title compound (12.4g, 78%).
    1H NMR (400 MHz, CDCl3): δ 7.36-7.35 (5H, m), 5.30 (2H, s), 4.21 (2H, q, J 7.1Hz), 4.15-4.04 (2H, m), 3.66-3.57 (3H, m), 2.83 (2H, d, J 4.3Hz), 2.23-2.05 (2H, m), 1.63-1.56 (2H, m), 1.29 (3H, t, J 7.1Hz), 0.88 (9H, s), 0.06 (6H, s).
    • DESCRIPTION 3 4-(1,2-Dihydroxyethyl)-4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester
  • Lithium borohydride (1g, 45mmol) was added portionwise to a solution of 4-[2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl]-piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester (Description 2; 11.2g, 24.1mmol) in tetrahydrofuran (75ml). The mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous sodium hydrogencarbonate solution, then partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated in vacuo to give the diol. This was dissolved in tetrahydrofuran (50ml). Tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 32ml, 32mmol) was added and the reaction stirred at room temperature for 1 hour. The mixture was partitioned between water and ethyl acetate. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 1, 2, 5 and 10% methanol/ethyl acetate, to give the title compound (5.4g, 73%).
    1H NMR (360 MHz, CDCl3): δ 7.39-7.29 (5H, m), 5.13 (2H, s), 3.82-3.70 (6H, m), 3.54 (1H, t, J 4.7Hz), 3.26-2.74 (5H, m), 1.73-1.54 (3H, m), 1.39-1.31 (1H, m).
    • DESCRIPTION 4 4-Hydroxy-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid benzyl ester
  • Diethyl azodicarboxylate (1.4g, 8.1mmol) was added to a solution of 4-(1,2-dihydroxyethyl)-4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (Description 3; 2g, 6.5mmol) and triphenylphosphine (2.4g, 9.1 mmol) in tetrahydrofuran (40ml). The reaction was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica, eluting with 1, 2 and 4% methanol / dichloromethane, to give the title compound (1.43g, 76%).
    1H NMR (400 MHz, CDCl3): δ 7.38-7.30 (5H, m), 5.13 (2H, s), 4.12-4.08 (1H, m), 4.02-3.99 (1H, m), 3.74-3.65 (5H, m), 3.39-3.33 (1H, m), 3.27-3.20 (1H, m), 1.89-1.87 (1H, m), 1.82-1.76 (1H, m), 1.59-1.54 (1H, m), 1.51-1.48 (2H, m).
    • DESCRIPTION 5 4-[2-(tert-Butyldimethylsilyloxy)-1-hydroxyethyl]-piperidine-4-dicarboxylic acid 1-(1,1-dimethylethyl) ester 4-ethyl ester
  • The title compound was prepared as described in Description 2 from piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester.
    1H NMR (360 MHz, CDCl3): δ 4.21 (2H, q, J 7.0Hz), 4.08-3.90 (2H, m), 3.75-3.50 (3H, m), 2.89-2.69 (2H, m), 2.19 (1H, m), 2.03 (1H, m), 1.57 (2H, dt, J 4.6, 13.0Hz), 1.45 (9H, s), 1.29 (3H, t, J 7.4Hz), 0.89 (9H, s), 0.06 (6H, s).
    • DESCRIPTION 6 4-(1,2-Dihydroxyethyl)-4-hydroxymethyl-piperidine-1-carboxylic acid 1,1-dimethylethyl ester
  • The title compound was prepared as described in Description 3 from the product of Description 5.
    1H NMR(400 MHz, CDCl3): δ 3.80-3.60 (6H, m), 3.55 (1H, m), 3.24-3.02 (3H, m), 1.73-1.48 (4H, m), 1.45 (9H, s), 1.33 (1H, m).
    • DESCRIPTION 7 4-Hydroxy-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid 1,1-dimethylethyl ester
  • The title compound was prepared as described in Description 4 from the product of Description 6.
    1H NMR (400 MHz, CDCl3): δ 4.11 (1H, dd, J 4.7, 10.2Hz), 4.01 (1H, dt, J 1.6, 4.7Hz), 3.74 (1H, d, J 8.6Hz), 3.73 (1H, dd, J 2.0, 10.7Hz), 3.67 (1H, d, J 8.6Hz), 3.63 (2H, m), 3.27 (1H, dt, J 6.3, 13.7Hz), 3.14 (1H, ddd, J 3.5, 9.0, 12.9Hz), 1.82 (1H, d, J 5.5Hz), 1.77 (1H, ddd, J 3.9, 9.0, 13.3Hz), 1.56 (1H, ddd, J 3.5, 6.3, 13.3Hz), 1.50-1.45 (2H, m), 1.46 (9H, s).
    • DESCRIPTION 8 (RS)-2-Oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride
  • 4-Hydroxy-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid 1,1-dimethylethyl ester (Description 7; 0.86g, 3.3mmol) was stirred overnight in 2M ethereal hydrogen chloride. The mixture was filtered and the solid dried to give the title compound (0.5g, 77%).
    1H NMR(360 MHz, MeOH-d 4): δ 4.15-4.06 (2H, m), 3.71-3.61 (3H, m), 3.69-3.13 (4H, m), 2.08-2.03 (1H, m), 1.80-1.74 (3H, m).
    • DESCRIPTION 9 (4R)-4-[(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carbonyloxy]-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid benzyl ester and (4S)4-[(1S,4R)4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carbonyloxy]-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid benzyl ester
  • (1S)-(-)-Camphanic chloride (335mg, 1.54mmol) was added to a stirred solution of 4-hydroxy-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid benzyl ester (Description 4; 300mg, 1.03mmol), triethylamine (0.4ml, 2.9mmol) and 4-N,N-dimethylaminopyridine (15mg, 0.12mmol) in dichloromethane (5ml). The mixture was stirred overnight and diluted with ethyl acetate and washed with saturated aqueous NaHCO3, 2M HCl and water. The organic phase was dried (Na2SO4) and concentrated. The residue was purified on silica (i-hexane:ethyl acetate) to give the title ester as a mixture of diastereoisomers (460mg). Diastereoisomers were separated on prep. HPLC (HIRPB, acetonitrile: 0.1% aq. trifluoroacetic acid) to give isomer A (190mg) and isomer B (195mg).
    • Isomer A: (4S)-isomer of the title compound
  • 1H NMR(400 MHz, CDCl3): δ 7.41 (5H, m), 5.13 (2H, s), 5.11 (1H, dd, J 1.6, 4.7Hz), 4.27 (1H, dd, J 4.7, 11.3Hz), 3.87 (1H, d, J 8.6Hz), 3.77 (1H, dd, J 2.0, 11.3Hz), 3.77-3.67 (2H, m), 3.67-3.58 (1H, m), 3.40 (1H, dt, J 6.3, 14.1Hz), 3.21 (1H, m), 2.38 (1H, ddd, J 4.3, 11.0, 13.7Hz), 2.05 (1H, dt, J 4.7, 9.4, 13.7Hz), 1.94 (1H, ddd, J 4.3, 10.6, 12.9Hz), 1.77-1.67 (2H, m), 1.66-1.56 (3H, m), 1.12 (3H, s), 1.07 (3H, s), 0.96 (3H, s).
    • Isomer B: (4R)-isomer of the title compound
  • 1H NMR(400 MHz, CDCl3): δ 7.40-7.29 (5H, m), 5.13 (2H, s), 5.11 (1H, dd, J 1.6, 4.7Hz), 4.27 (1H, dd, J 5.1, 11.3Hz), 3.87 (1H, d, J 8.6Hz), 3.77-3.66 (3H, m), 3.40 (1H, dt, J 6.3, 14.4Hz), 3.21 (1H, m), 2.43 (1H, ddd, J 4.3, 10.6, 13.3Hz), 2.01 (1H, ddd, J 4.7, 9.0, 13.3Hz), 1.93 (1H, ddd, J 4.3, 10.6, 12.9Hz), 1.80-1.65 (3H, m), 1.64-1.56 (3H, m), 1.12 (3H, s), 1.04 (3H, s), 0.97 (3H, s).
    • DESCRIPTION 10 (1S,4R)4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4R)-2-oxa-8-aza-spiro[4.5]dec-4-yl ester trifluoroacetate
  • A mixture of isomer B of the product of Description 9 (130mg, 0.27mmol), palladium on carbon (10%, 73mg), trifluoroacetic acid (0.1ml) and ethanol (20ml) was stirred at room temperature under H2 atmosphere (balloon) for 30 minutes, and then filtered through a pad of Celite™ and concentrated to give the title compound (130mg).
    1H NMR (400 MHz, MeOH-d 4): δ 5.19 (1H, dd, J 2.0, 4.7Hz), 4.29 (1H, dd, J 5.0, 10.8Hz), 3.86 (1H, d, J 8.8Hz), 3.76 (1H, dd, J 2.0, 11.1Hz), 3.69 (1H, d, J 8.8Hz), 3.26-3.11 (3H, m), 3.03 (1H, ddd, J 3.5, 8.8, 12.6Hz), 2.50 (1H, ddd, J 6.1, 12.6, 15.2Hz), 2.09-1.90 (3H, m), 1.98-1.74 (3H, m), 1.63 (1H, m), 1.64-1.56 (3H, m), 1.10 (3H, s), 1.08 (3H, s), 0.97 (3H, s).
    • DESCRIPTION 11 2-[1-{(2R,3R,4R)2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde
  • N-Methylmorpholine N-oxide (1g, 8.6mmol) and osmium tetroxide (2ml, 2.5% solution in tert-butanol) were added to a solution of (2R,3R,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-4-vinyl-tetrahydropyran (see Example 147 in WO 00/56727 ; 2g, 4.3mmol) in tetrahydrofuran (25ml) and water (10ml). The mixture was stirred at room temperature for one hour before sodium periodate (9g, 43mmol) was added. This mixture was stirred for 45 minutes and then filtered through Celite™. The filtrate was diluted with ethyl acetate (50ml) and washed with brine. The organic extracts were dried and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate / iso-hexanes to give the title compound (1.6g, 80%).
    1H NMR (400 MHz, CDCl3): δ 9.47 (1H, s), 7.70 (1H, s), 7.27 (2H, s), 7.15-7.12 (2H, m), 6.99-6.95 (2H, m), 4.97 (1H, q, J 6.6Hz), 4.28-4.16 (2H, m), 3.60-3.58 (1H, m), 3.00 (1H, dd, J 7.3, 10.6Hz), 2.80-2.70 (1H,m), 1.85-1.81 (2H, m), 1.39 (3H, d, J 6.6Hz).
    • DESCRIPTION 12 (1S,4R)4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4S)-8 {(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-yl ester
  • Palladium hydroxide (20% on carbon, 20mg) was added as a slurry in ethanol to a solution of isomer A of the product of Description 9 (120mg, 0.25mmol) in ethanol (5ml). The mixture was hydrogenated in a Parr apparatus (45 psi) for 30 minutes then filtered through Celite™ and washed with ethanol. The filtrate was concentrated in vacuo. The residue and 2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde (Description 11; 232mg, 0.5mmol) were suspended in 1,2-dichloroethane (10ml) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (105mg, 0.5mmol) was added and the reaction stirred overnight at room temperature. The mixture was partitioned between dichloromethane and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative thin layer chromatography, eluting with 7.5% methanol/dichloromethane, to give the title compound (138mg, 70%).
    m/z (ES+) 786 (M+H)+.
    • DESCRIPTION 13 (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4R)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-yl ester
  • Solid sodium triacetoxyborohydride (107mg, 0.504mmol) was added to a stirred mixture of 2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde (Description 11; 121mg, 0.36mmol), (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4R)-2-oxa-8-aza-spiro[4.5]dec-4-yl ester trifluoroacetate (Description 10; 130mg), triethylamine (0.1ml, 0.72mmol) and dichloromethane (3ml) at room temperature. The mixture was stirred for 45 minutes, quenched with saturated aqueous NaHCO3 and extracted into dichloromethane. The organic extract was dried (Na2SO4) and concentrated. The residue was purified by preparative TLC (dichloromethane:methanol) to give the title compound (100mg). The HCl salt was prepared and recrystallised from ethyl acetate:methanol.
    1H NMR (400 MHz, CDCl3): δ 7.67 (1H, s), 7.17 (2H, s), 7.02-6.89 (4H, m), 4.98 (1H, m), 4.95 (1H, q, J 6.3Hz), 4.23-4.08 (3H, m), 3.68 (1H, d, J 8.6Hz), 3.66 (1H, dd, J 1.6, 9.4Hz), 3.58-3.45 (2H, m), 2.50-2.33 (3H, m), 2.25-1.83 (8H, m), 1.81-1.65 (2H, m), 1.57-1.40 (3H, m), 1.36 (3H, d, J 6.6Hz), 1.11 (3H, s), 1.02 (3H, s), 0.94 (3H, s); m/z (ES+) 786 (M+H)+.
    • DESCRIPTION 14 (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4R)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-yl ester (i) (2R,3R,4R)2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-carbaldehyde a) (3-Bromo-4-fluorophenyl)acetic acid 3-bromopropyl ester
  • (3-Bromo-4-fluorophenyl)acetyl chloride (30.2g, 0.12mol) was dissolved in dichloromethane (70mL) and the solution was cooled to 0°C. 3-Bromopropanol (24.7g, 0.177mol) in dichloromethane (30mL) was added dropwise and the mixture was stirred at room temperature overnight. The mixture was washed with water, brine, dried (MgSO4) and the solvent was removed in vacuo. The resulting oil was purified on silica using 5-10% ethyl acetate in hexane to give the product (36g, 82%).
    1H NMR (400 MHz, CDCl3): δ 7.48 (1H, dd, J 2.3, 6.5Hz), 7.19 (1H, ddd, J 2.3, 4.6, 8.5Hz), 7.10 (1H, t, J 8.4Hz), 4.25 (2H, t, J 6.1Hz), 3.58 (2H, s), 3.41 (2H, t, J 6.6Hz), 2.17 (2H, quintet, J 6.2Hz).
    • b) (3-Bromo-4-fluorophenyl)-3,4,5,6-tetrahydrohydropyran-2-one
  • Sodium hydride (4.62g, 0.11mol) was suspended in dimethylformamide (200mL) and the suspension was warmed to 60°C. To this was added dropwise (3-bromo-4-fluoro)phenylacetic acid 3-bromopropyl ester (from step a) above; 35.3g) in dimethylformamide (20mL) and the mixture was stirred for 30min until all gas evolution ceased. The mixture was cooled and quenched with water (10mL) cautiously, and then diluted with water (1500mL) and extracted with ethyl acetate (3x100mL). The pooled organic extracts were washed with brine, dried (MgSO4) and evaporated. The crude residue was purified by chromatography on silica using 10-30% ethyl acetate in hexane as eluant to give the lactone (17.1g, 63%).
    1H NMR (400 MHz, CDCl3): δ 7.44 (1H, dd, J 2.3, 6.2Hz), 7.17 (1H, ddd, J 2.2, 4.6, 8.5Hz), 7.07 (1H, t, J 8.4Hz), 4.45 (2H, m), 3.72 (1H, dd, J 6.8, 10.2Hz), 2.30 (1H, m), 2.03 (3H, m).
    • c) (±) 3-Bromo-(3-bromo-4-fluorophenyl)-3,4,5,6-tetrahydrohydropyran-2-one
  • (3-Bromo-4-fluorophenyl)-3,4,5,6-tetrahydrohydropyran-2-one (from step b) above; 14.82g, 0.054mol) was dissolved in carbon tetrachloride (200mL) and benzoyl peroxide (100mg) and N-bromosuccinimide (11.63g, 0.065mol) were added. The mixture was heated cautiously to reflux and maintained at reflux for 3h. The mixture was cooled, filtered and concentrated. The crude residue was purified by chromatography on silica using 10-100% ethyl acetate in hexane as eluant to give the bromide (17.9g, 95%).
    1H NMR (400 MHz, CDCl3): δ 7.84 (1H, dd, J 2.6, 6.3Hz), 7.57 (1H, ddd, J 2.6, 4.4, 8.8Hz), 7.13 (1H, t, J 8.6Hz), 4.62 (1H, m), 4.42 (1H, m), 2.80-2.60 (2H, m), 2.38 (1H, m), 2.30 (1H, m), 1.88 (1H, m).
    • d) 3-(3-Bromo-4-fluorophenyl)-5,6-dihydropyran-2-one
  • (±) 3-Bromo-(3-bromo-4-fluorophenyl)-3,4,5,6-tetrahydrohydropyran-2-one (from step c) above; 17.9g, 0.051mol) was dissolved in tetrahydrofuran (200mL) and lithium bromide (6.6g, 0.076mol) and lithium carbonate (5.6g, 0.076mol) were added. The mixture was heated at reflux for 3h, then cooled. The mixture was filtered to remove inorganic material. The solvent was removed in vacuo and the crude residue was purified by chromatography on silica using 10-50% ethyl acetate in hexane as eluant to give the enone (11.36g, 82%).
    1H NMR (400 MHz, CDCl3): δ 7.68 (1H, dd, J 2.8, 6.6Hz), 7.41 (1H, ddd, J 2.2, 4.6, 8.6Hz), 7.11 (1H, t, J 8.4Hz), 7.00 (1H, t, J 4.6Hz), 4.49 (2H, t, J 6.3Hz), 2.64 (2H, dt, J 4.6, 6.2Hz).
    • e) (±) 3-(3-Bromo-4-fluorophenyl)-4-vinyl-3,4,5,6-tetrahydrohydropyran-2-one
  • Copper iodide (375mg, 5 mol%) was suspended in tetrahydrofuran (300mL) and the mixture was cooled to -78°C. To this mixture was added vinylmagnesium chloride (25mL, 1.7M) followed by dropwise addition of 3-(3-bromo-4-fluorophenyl)-5,6-dihydropyran-2-one (from step d) above; 10.64g, 0.039mol) and trimethylsilyl chloride (4.97mL, 0.039mol). The reaction progress was monitored by thin layer chromatography. The reaction mixture was quenched by pouring, via double-ended needle, onto ammonium chloride (saturated aqueous solution). The mixture was concentrated in vacuo to remove tetrahydrofuran and the residue was extracted with ethyl acetate (3x200mL). The pooled organic extracts were washed with brine, dried (MgSO4) and evaporated. The crude residue re-dissolved in tetrahydrofuran and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3mL) was added. This solution was stirred for 4h. Tetrahydrofuran was removed in vacuo and the residue was purified by chromatography on silica using 30-50% ethyl acetate in hexane as eluant to give the vinyl lactone (11.5g, 80%).
    1H NMR (400 MHz, CDCl3): δ 7.37 (1H, d, J 6.6Hz), 7.09 (2H, d, J 7.5Hz), 5.61 (1H, d, J 10.3Hz), 4.92 (1H, d, 17.1Hz), 4.57- 4.43 (2H, m), 3.44 (1H, d, J 10.9Hz), 2.78 (1H, m), 2.16 (1H, m), 1.96 (1H, m).
    • f) (±) 3-(3-Bromo-4-fluorophenyl)-4-vinyltetrahydropyran-2-ol
  • (±) 3-(3-Bromo-4-fluorophenyl)-4-vinyl-3,4,5,6-tetrahydrohydropyran-2-one (from step e) above; 9.5g, 0.032mol) was dissolved in ethanol (90mL) and cerium (III) chloride was added. The resulting solution was cooled to -30°C and sodium borohydride (1.2g, 0.032mol) was added portionwise. The mixture was stirred for 30min and was then quenched with acetone (18m). The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and water. The mixture was filtered through Celite™ to remove inorganic material. The combined organic extracts were washed with brine and dried (MgSO4). The solvent was removed in vacuo to give the lactol as a yellow solid (9.07g, 94%).
    1H NMR (400 MHz, CDCl3) 3:2 mixture: δ 7.48 (0.4H, m), 7.37 (0.6H, m), 7.20-7.16 (0.4H, m), 7.12-7.00 (1.6H, m), 5.51-5.40 (1H, m), 5.16 (0.4H, s), 4.96-4.82 (2H, m), 4.73 (0.6H, dd, J 2.6, 8.1Hz), 4.22-4.10 (1H, m), 3.75-3.67 (1H, m), 2.97 (0.4H, m), 2.84 (0.6H, m), 2.71 (0.4H, dd, J 2.8, 11.8Hz), 2.54-2.45 (0.6H, m), 2.40-2.32 (1H, m), 1.80-1.60 (2H, m).
    • g) (2R,3R,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo4-fluorophenyl)-4-vinyltetrahydropyran
  • (±) 3-(3-Bromo-4-fluorophenyl)-4-vinyltetrahydropyran-2-ol (from step f) above; 10.32g, 0.034mol), (1R)-3,5-bis(trifluoromethyl)phenylethanol (11g, 0.042mol), Amberlyst™ (5g) and molecular sieves (8g) were suspended in dichloromethane (20mL) and the mixture was shaken at 40°C for 3 days. The resulting yellow solution was filtered, concentrated in vacuo and was purified by chromatography on silica using 1-5% ethyl acetate in hexane as eluant to give a mixture of isomers 1-3 (which were retained) and the desired isomer 4 (3.6g, 20%) as a colourless oil.
    1H NMR (400 MHz, CDCl3): δ 7.69 (1H, s), 7.26-7.21 (3H, m), 6.98 (1H, t J 8.4Hz), 6.91 (1H, m), 5.43 (1H, ddd, J 7.1, 10.5, 17.4Hz), 4.95 (1H, q, J 6.6Hz), 4.83 (1H, d, J 10.6Hz), 4.80 (1H, d, J 17.4Hz), 4.16 (1H, d, J 8.3Hz), 4.14 (1H, m), 3.56 (1H, m), 2.49 (1H, dd, J 8.3, 11.6Hz), 2.38 (1H, m), 1.75-1.60 (2H, m), 1.40 (3H, d, J 6.6Hz).
    • h) (2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-carbaldehyde
  • (2R,3R,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)-4-vinyltetrahydropyran (from step g); 0.5g, 0.924mol) was dissolved in dichloromethane (10mL) and methanol (7mL) and ozone was bubbled through the solution at -78°C until a blue coloration persisted. The solution was purged with nitrogen and dimethyl sulfide (0.6mL) was added dropwise. The mixture was allowed to stir overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The combined organic phase was dried (MgSO4) and the solvent was evaporated. The residue was purified by chromatography on silica using 10-20% ethyl acetate in hexane as eluant to afford the product aldehyde as a colourless oil (170mg, 34%).
    1H NMR (CDCl3): δ 1.42 (3H, d, J 6.6Hz), 1.78-1.89 (2H, m), 2.68-2.74 (1H, m), 3.01 (1H, dd, J 7.1, 10.3Hz), 3.59-3.64 (1H, m), 4.10-4.19 (1H, m), 4.28 (1H, d, J 7.1Hz), 4.97 (1 H, q, J 6.6Hz), 7.03 (1H, t, J 8.3Hz), 7.08-7.11 (1H, m), 7.31 (2H, s), 7.39 (1H, dd, J 2.2, 6.6Hz), 7.72 (1H, s), 9.51 (1H, d, J 1.5Hz).
    • (ii) (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4R)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-yl ester
  • (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4R)-8-aza-8-benzyloxycarbonyl-2-oxa-spiro[4.5]dec-4-yl ester (Description 9, isomer B; 100mg, 0.21mmol) was dissolved in methanol (20ml) and trifluoroacetic acid (0.1ml) and Pd (10% on carbon, 20mg) were added under nitrogen. The mixture was purged with hydrogen gas and stirred for 30 min under a balloon of hydrogen. The mixture was purged with nitrogen and filtered to remove catalyst; solvents were removed in vacuo to give the amine as a colourless oil.
    m/z 338 (M+ + 1, 100%).
    The amine salt was dissolved in dichloroethane (3ml) and triethylamine (0.056ml, 0.4mmol) followed by (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-carbaldehyde (Description 14(i); 130mg, 0.25mmol) and sodium triacetoxyborohydride (63mg, 0.318mmol) and the resulting mixture was stirred for 30min. The mixture was then diluted with dichloromethane and washed with sodium bicarbonate (saturated aqueous solution). The organic extracts were pooled, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel using 1-5% methanol in dichloromethane as eluant. This afforded the product as a white solid (150mg, 83%).
    This was further purified by recrystallisation of the HCl salt from ether-ethyl acetate to give the product as white crystals (140mg).
    1H NMR (500MHz, CDCl3): δ 7.69 (1H, s), 7.22 (1H, dd overlapped, J 2.0Hz), 7.21 (3H, s), 6.98 (1H, t, J 8.3Hz), 6.92-6.89 (1H, m), 5.00 (1H, dd, J 1.3, 4.5Hz), 4.95 (1H, q, J 6.6Hz), 4.18 (1H, dd, J 11.5, 4.7Hz), 4.17-4.13 (1H, m), 4.10 (1H, d, J 8.3Hz), 3.72 (1H, d, J 8.3Hz), 3.66 (1H, d, J 11.0Hz), 3.54 (1H, d, J 8.5Hz), 3.50 (1H, br d), 2.43-2.33 (3H, m), 2.17-2.11 (1H, m), 2.07-1.83 (9H, m), 1.72-1.62 (2H, m), 1.50-1.38 (3H, m), 1.38 (3H, d, J 6.6Hz), 1.11 (3H, s), 1.02 (3H, s), 0.94 (3H, s); m/z (ES+) 864 (M++1, 100%), 866 (M++1, 95%).
    • DESCRIPTION 15 [(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methanol
  • Sodium borohydride (24mg, 0.63mmol) was added to solution of 2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-carbaldehyde (see Example 2 in WO 02/16344 ; 107mg, 0.23mmol) in methanol (3ml). The mixture was stirred for 30 minutes then quenched with saturated aqueous NaHCO3 and extracted into ethyl acetate. The combined organic extracts were dried and concentrated to give the title compound (104mg).
    1H NMR (360 MHz, CDCl3): δ 7.70 (1H, s), 7.21 (2H, s), 7.05 (1H, m), 6.97 (1H, ddd, J 1.8, 7.4, 10.9Hz), 6.79 (1H, m), 4.97 (1H, q, J 6.7Hz), 4.22-4.11 (2H, m), 3.55 (1H, dt, J 2.5, 12.3Hz), 3.39 (1H, m), 3.24 (1H, m), 2.57 (1H, dd, J 8.4, 11.2Hz), 1.94-1.78 (2H, m), 1.68 (1H, m), 1.39 (3H, d, J 6.7Hz), 1.18 (1H, m).
    • DESCRIPTION 16 Methanesulfonic acid [(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methyl ester
  • Methanesulfonyl chloride (50µl, 0.63mmol) was added to a mixture of [(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methanol (Description 15; 235mg, 0.49mmol), triethylamine (133m, 0.97mmol), 4-N,N-dimethylaminopyridine (3mg, 0.02mmol) and dichloromethane (5ml) at 0°C. The mixture was stirred for 30 minutes, then quenched with saturated aqueous NaHCO3 and extracted into dichloromethane. The combined organic extracts were dried and concentrated. The product was used in the next step without further purification.
    1H NMR (400 MHz, CDCl3): δ 7.70 (1H, s), 7.20 (2H, s), 7.09 (1H, dt, J 8.6, 9.8Hz), 6.88 (1H, ddd, J 2.0, 7.4, 11.0Hz), 6.81 (1H, m), 4.97 (1H, q, J 6.7Hz), 4.21-4.12 (2H, m), 3.95 (1H, dd, J 3.1, 9.8Hz), 3.80 (1H, dd, J 7.4, 10.2Hz), 3.55 (2H, dt, J 2.4, 12.1Hz), 2.90 (3H, s), 2.58 (1H, dd, J 8.2, 11.7Hz), 2.12 (1H, m), 1.86 (1H, m), 1.78-1.66 (1H, m), 1.39 (3H, d, J 6.7Hz).
    • DESCRIPTION 17 1-Oxa-8-azaspiro[4.5]decane Hydrochloride (i) 1,1-Dimethylethyl 4-hydroxy-4-(3-trimethylsilyloxypropynyl)-1-piperidinecarboxylate
  • Trimethyl(2-propynyloxy)silane (11.54m, 9.62g, 75mmol) was added dropwise to a stirred, cooled (-5°C) solution of ethyl magnesium bromide (1M in tetrahydrofuran, 75ml, 75mmol) in tetrahydrofuran (150ml), maintaining the internal temperature below 0°C. The mixture was stirred at 0°C for 30 minutes, then at room temperature for 90 minutes. The mixture was cooled to -5°C and 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (15.0g, 75mmol) was added slowly, maintaining the internal temperature below 0°C. The mixture was stirred at 0°C for 3 hours then at room temperature for 96 hours. Saturated aqueous ammonium chloride (300ml), water (100ml) and ethyl acetate (300ml) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (200ml) and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (24.4g, 100%).
    1H NMR(400 MHz, CDCl3): δ 4.36 (2H, s), 3.80-3.70 (2H, m), 3.35-3.25 (2H, m), 1.95-1.85 (2H, m), 1.78-1.60 (3H, m), 1.48 (9H, s), 0.2 (9H, s).
    • (ii) 1,1-Dimethylethyl 4-hydroxy4-(3-hydroxypropynyl)-1-piperidinecarboxylate
  • Tetrabutylammonium fluoride (1M in tetrahydrofuran, 80ml, 80mmol) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-trimethylsilyloxypropynyl)-1-piperidinecarboxylate (from step (i) above; 24.4g, 75mmol) in tetrahydrofuran (300ml) and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and water (200ml) was added. The mixture was extracted with ethyl acetate (2 x 200ml) and the combined organic fractions were washed with water (2 x 200ml) and brine (200ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (16.8g, 88%).
    1H NMR (400 MHz, CDCl3): δ 4.32 (2H, s), 3.80-3.68 (2H, m), 3.32-3.22 (2H, m), 1.93-1.83 (2H, m), 1.75-1.65 (2H, m), 1.62 (1H, br s), 1.46 (9H, s).
    • (iii) 1,1-Dimethylethyl 4-hydroxy-4-(3-hydroxypropyl)-1-piperidinecarboxylate
  • Palladium on carbon (5%, 800 mg) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxypropynyl)-1-piperidinecarboxylate (from step (ii) above; 8.37g, 32.8mmol) in ethanol (400ml), acetic acid (40ml) and water (5ml) and the mixture was shaken under an atmosphere of hydrogen (40 psi) for 20 hours. The mixture was filtered through Hyflo™ and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50 increasing to 0:100), to give the title compound (4.84g, 57%).
    1H NMR (400 MHz, CDCl3): δ 3.85-3.75 (2H, m), 3.70 (2H, t, J 6Hz), 3.18 (2H, br t, J 14Hz), 2.00 (2H, br s), 1.73-1.65 (2H, m), 1.63-1.48 (6H, m), 1.46 (9H, s).
    • (iv) 1,1-Dimethylethyl 1-oxa-8-azaspiro[4.5]decane-8-carboxylate
  • A solution of diethyl azodicarboxylate (3.35ml, 21.3mmol) in tetrahydrofuran (50ml) was added over 15 minutes to a stirred, cooled (0°C) solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxypropyl)-1-piperidinecarboxylate (from step (iii) above; 4.6g, 17.8mmol) and triphenylphosphine (5.58g, 21.3mmol) in tetrahydrofuran (150ml) and the mixture was stirred at 0°C for 1 hour, then at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25 increasing to 50:50), to give the title compound (3.18g, 70%).
    1H NMR (400 MHz, CDCl3): δ 3.83 (2H, t, J 7Hz), 3.63-3.53 (2H, m), 3.38-3.28 (2H, m), 1.93 (2H, quin., J 7Hz), 1.69 (2H, t, J 7Hz), 1.63-1.48 (4H, m), 1.46 (9H, s); m/z (ES+) 242 (M+1).
    • (v) 1-Oxa-8-azaspiro[4.5]decane Hydrochloride
  • Methanolic hydrogen chloride (3M, 20ml) was added over 10 minutes to a stirred, cooled (0°C) solution of 1,1-dimethylethyl 1-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (iv) above, 3.18g, 13.2mmol) in methanol (10ml) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give the title compound (2.29g, 98%).
    1H NMR (400 MHz, CDCl3): δ 3.85 (2H, t, J 7Hz), 3.27-3.15 (4H, m), 1.98 (2H, quin., J 7Hz), 1.86-1.75 (6H, m); m/z (ES+) 142 (M+1).
    • DESCRIPTION 18 2,2-Dimethyl-1-oxa-8-azaspiro[4.5]decane (i) 1,1-Dimethylethyl 4-(3-ethoxy-3-oxo-1-propynyl)-4-hydroxy-1-piperidinecarboxylate
  • n-Butyllithium (175ml, 0.28mol) was added dropwise over 45 minutes to a stirred, cooled (-70°C) solution of ethyl propiolate (32ml, 0.32mol) in tetrahydrofuran (250ml). The mixture was stirred at -70°C for 10 minutes, then a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (18.6g, 0.093 mol) in tetrahydrofuran (250ml) was added dropwise over 1 hour maintaining the internal temperature below -70°C. The mixture was stirred at -70°C for 1 hour and then acetic acid (21ml) in tetrahydrofuran (50ml) was added. The mixture was warmed to room temperature and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (300ml) and ethyl acetate (650ml) were added and the layers were separated. The aqueous fraction was extracted with ethyl acetate (2 x 650ml) and the combined organic fractions were washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a short silica gel column, eluting with 1:1 isohexane:ethyl acetate, to give the title compound (29.2g, contains trace impurity).
    1H NMR (400 MHz, CDCl3): δ 4.24 (2H, q, J 7Hz), 3.73-3.68 (2H, m), 3.38-3.31 (2H, m), 1.98-1.91 (2H, m), 1.80-1.72 (2H, m), 1.46 (9H, s), 1.31 (3H, t, J 7Hz); m/z (ES+) 298 (M+1).
    • (ii) 1,1-Dimethylethyl 4-(3-ethoxy-3-oxoprop-1-yl)-4-hydroxy-1-piperidinecarboxylate
  • Palladium on carbon (5%, 1 g) in water (10ml) was added to a solution of 1,1-dimethylethyl 4-(3-ethoxy-3-oxo-1-propynyl)-4-hydroxy-1-piperidinecarboxylate (from step (i) above; 14.6g, 0.046 mol) in ethanol (200ml) and the mixture was shaken under hydrogen (45 psi) for 90 minutes. The mixture was filtered through a glass fibre pad and the solvent was evaporated under reduced pressure to give the title compound.
    1H NMR (400MHz, CDCl3) δ 4.14 (2H, q, J 7Hz), 3.80 (2H, br s), 3.20-3.11 (2H, m), 2.45 (2H, t, J 7Hz), 1.81 (2H, t, J 7Hz), 1.58-1.42 (4H, m), 1.45 (9H, s), 1.26 (3 H, t, J 7Hz); m/z (ES+) 302 (M+1).
    • (iii) 1,1-Dimethylethyl 1-oxa-2-oxo-8-azaspiro[4.5]decane-8-carboxylate
  • p-Toluenesulfonic acid (1.75g, 9.2mmol) was added to a solution of 1,1-dimethylethyl 4-(3-ethoxy-3-oxoprop-1-yl)-4-hydroxy-1-piperidinecarboxylate (from step (ii) above; 27.63g, 0.092mol) in toluene (250ml) and the mixture was heated under reflux for 3 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. Water (400ml) and ethyl acetate (400ml) were added and the layers were separated. The aqueous fraction was extracted with ethyl acetate (200ml). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (20.86g, 88%).
    1H NMR (400 MHz, CDCl3): δ 3.84-3.79 (2H, m), 3.26 (2H, br t), 2.62 (2H, t, J 7Hz), 2.05 (2H, t, J 7Hz), 1.83-1.79 (2H, m), 1.68-1.62 (2H, m), 1.46 (9H, s); m/z (ES+) 256 (M+1).
    • (iv) 1,1-Dimethylethyl 4-hydroxy-4-(3-hydroxy-3-methylbut-1-yl)-1-piperidinecarboxylate
  • 1,1-Dimethylethyl 1-oxa-2-oxo-8-azaspiro[4.5]decane-8-carboxylate (from step (iii) above; 5.0g, 19.58mmol) in tetrahydrofuran (150ml) was added dropwise over 45 min. to a stirred, cooled (0 °C) solution of methyl magnesium chloride (3M in tetrahydrofuran, 19.58m, 58.75mmol) in tetrahydrofuran (150ml). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into saturated aqueous ammonium chloride (200ml) and extracted with ethyl acetate (200ml). The organic fraction was washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate, to give the title compound (3.9g, 69%).
    1H NMR(400 MHz, CDCl3): δ 3.85-3.75 (2H, m), 3.20-3.10 (2H, m), 2.55-2.25 (2H, m), 1.58-1.45 (6H, m), 1.46 (9H, s), 1.24 (6H, s); m/z (ES+) 214 (M+1-C4H8-H2O).
    • (v) 2,2-Dimethyl-1-oxa-8-azaspiro[4.5]decane
  • Trifluoroacetic acid (10m) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxy-3-methylbut-1-yl)-1-piperidinecarboxylate (from step (iv) above; 3.9g, 13.57mmol) in dichloromethane (10ml) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (90:10:1) to give the title compound (2.04g, 89%).
    1H NMR (400MHz, CDCl3): δ 3.27-3.17 (4H, m), 1.95-1.82 (6H, m), 1.70 (2H, d, J 13.4Hz), 1.22 (6H, s); m/z (ES+) 170 (M+1).
    • DESCRIPTION 19 6-Oxa-2-azaspiro[3.4]octan-8-ol (i) 1-Benzyloxycarbonyl-3-azetidinecarboxylic acid
  • 3-Azetidinecarboxylic acid (4.0g, 39.6 mmol) was dissolved in 1N sodium hydroxide solution (40mL) and cooled to 0°C. Benzyl chloroformate (5.9mL, 41mmol) was added followed by further 1N sodium hydroxide solution (41mL) dropwise. The mixture was stirred vigorously for 16hrs then made acidic with 2N hydrochloric acid. This suspension was extracted with dichloromethane (2x100mL) and the extracts dried over MgSO4. Concentration yielded the title compound (9.3g, 39.6mmol, 100%).
    1H NMR (400MHz, CDCl3): δ 7.37-7.29 (5H, m), 5.10 (2H, s), 4.21 (4H, d, J 7.5Hz), 3.43 (1H, quintet, J 7.5 Hz).
    • (ii) Methyl 1-benzyloxycarbonyl-3-azetidinecarboxylate
  • 1-Benzyloxycarbonyl-3-azetidinecarboxylic acid (from step (i); 9.3g, 39.6mmol) was dissolved in methanol (100mL) and toluene (100mL), and cooled to 0°C. A solution of 2M trimethylsilyldiazomethane in hexanes was then added dropwise until bubbling had ceased and the yellow colour persisted. Acetic acid was then added dropwise until the yellow colour disappeared. Concentration of the solution yielded the title compound as an oil (9.48g, 38mmol, 96%).
    1H NMR (400MHz, CDCl3): δ 7.36-7.31 (5H, m), 5.10 (2H, s), 4.19 (4H, d, J 7.8Hz), 3.75 (3H, s), 3.39 (1H, quintet, J 7.8Hz).
    • (iii) Benzyl 3-(1,2-dihydroxyethyl)-3-(hydroxymethyl)azetidine-1-carboxylate
  • Methyl 1-benzyloxycarbonyl-3-azetidinecarboxylate (from step (ii); 10.1g, 40mmol) was dissolved in tetrahydrofuran (120mL) and cooled to -78°C. A solution of lithium hexamethyldisilazide in tetrahydrofuran (1M, 58mL, 58mmol) was slowly added and the solution warmed to 0°C. After 15 mins. at this temperature, the resulting solution was cooled back to -78°C and tert-butyldimethylsilyloxy acetaldehyde was added and stirred to room temperature over 2hrs and quenched with water (200mL). This suspension was extracted with ethyl acetate (2x200mL). The extracts were dried (MgSO4) and concentrated. The residue was flushed through silica with 25% ethyl acetate in hexanes to give a 1:2 mixture of 1-benzyl 3-methyl 3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxyethyl)azetidine-1,3-dicarboxylate : starting material (4.24g).
    This mixture was dissolved in tetrahydrofuran (30mL) and treated with lithium borohydride (395mg, 18mmol). After 2hrs at room temperature, the mixture was quenched with 1N sodium hydroxide solution (100mL) and extracted with ethyl acetate (2x100mL). The extracts were dried (MgSO4) and concentrated to give crude benzyl 3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxyethyl)-3-(hydroxylmethyl) azetidine-1-carboxylate. This was dissolved in tetrahydrofuran (100mL) and treated with 1M tetra-n-butylammonium fluoride in tetrahydrofuran (10mL, 10mmol). After stirring for lhr at room temperature, water (200mL) was added and the mixture extracted with ethyl acetate (2x200mL). The combined extracts were dried (MgSO4) and concentrated. The residue was purified by silica chromatography to give the title compound as an oil (956mg, 3.4mmol).
    1H NMR (400 MHz, CDCl3): δ 7.37-7.29 (5H, m), 5.09 (2H, s), 3.96-3.64 (9H, m), 3.13 (2H, br m), 1.69 (1H, br m).
    • (iv) Benzyl 8-hydroxy-6-oxa-2-azaspiro[3.4]octane-2-carboxylate
  • Benzyl 3-(1,2-dihydroxyethyl)-3-(hydroxymethyl)azetidine-1-carboxylate (from step (iii); 956mg, 3.4mmol) was dissolved in dichloromethane (150mL) and dibutyltin oxide (17mg) was added. p-Toluenesulfonyl chloride (686mg, 3.6mmol) was added and the solution was cooled to 0°C. Triethylamine (520µL, 3.75mmol) was added dropwise and the solution was then allowed to stir at ambient temperature for 16hrs. Further triethylamine (260µL, 1.9mmol) was added and after stirring for 2hrs, water (250mL) was added. The mixture was extracted with dichloromethane (2x250mL), and the extracts dried (MgSO4) then concentrated. The residue was purified by silica chromatography to give the title compound as an oil (456mg, 1.7mmol, 51%).
    1H NMR (400 MHz, CDCl3): δ 7.37-7.29 (5H, m), 5.10 (2H, s), 4.31-4.27 (2H, m), 3.97 (2H, dd, J 9.1, 24Hz), 3.94-3.91 (1H, m), 3.86 (1H, d, J 9.5Hz), 3.85 (2H, dd, J 9.1, 20Hz), 3.74 (1H, dd, J 1.9, 10.2Hz), 1.95 (1H, d, J 4.4Hz).
    • (v) 6-Oxa-2-azaspiro[3.4]octan-8-ol
  • Benzyl 8-hydroxy-6-oxa-2-azaspiro[3.4]octane-2-carboxylate (from step (iv); 456mg, 1.7mmol) was dissolved in methanol (20mL) and 10% palladium on carbon (50mg) added. This suspension was hydrogenated at 20psi hydrogen for 2hrs then filtered. The filtrate was concentrated to give the title compound as a gum (214mg, 1.66mmol, 98% yield).
    m/z (ES+) 130 (M+H).
    • DESCRIPTION 20 4-Hydroxy-1-oxa-8-azaspiro[4.5]decane (i) tert-Butyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}propylidene)piperidine-1-carboxylate
  • 3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)(triphenyl)phosphonium bromide (J. Med Chem 1990, 33, 1958) (5.15g, 0.01mol) was suspended in toluene and azeotroped to remove any moisture. It was then suspended in 1,2-dimethoxyethane (20mL) and n-butyllithium (7.0mL, 1.6M. 0.011mol) was added dropwise until a yellow coloration persisted. tert-Butyl 4-oxopiperidine-1-carboxylate (2g, 0.01mol) was added and the mixture was heated at reflux overnight. The cooled mixture was diluted with water and extracted with ethyl acetate (2 x 50mL), dried (MgSO4) and concentrated in vacuo. The crude yellow oil was purified on silica using 10-30% ethyl acetate in iso-hexane as eluant.
    1H NMR (500 MHz, CDCl3): δ 0.01 (6H, s), 0.84 (9H, s), 2.06-2.18 (4H, m), 2.20 (2H, t, J 7.0Hz), 3.33 (4H, multiplet centre (mc)), 3.53 (2H, t, J 7.0Hz), 5.24 (1H, t, J 7.2Hz); m/z (ES+) 256 (M++1-100, 100%).
    • (ii) tert-Butyl 4-(1,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate
  • tert-Butyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}propylidene)piperidine-1-carboxylate (from step (i) above; 0.9g) was dissolved in tetrahydrofuran (1mL); tetra-n-butylammonium fluoride (2.5mL, 1M in THF) was added and the mixture was stirred for 30 min until tlc analysis (50:50 ethyl acetate:hexane) showed that all starting material had reacted. This mixture was concentrated in vacuo. The crude product was re-dissolved in tert-butanol (5mL) and water (1mL) and N-methylmorpholine N-oxide (322mg) was added and stirred until dissolved. Osmium tetroxide (0.15m, 2.5% in t-butanol) was added and the mixture was stirred for 12h. This mixture was concentrated in vacuo. The crude product was purified by chromatography on silica using 1-6% methanol in dichloromethane as eluant to afford the product (480mg).
    1H NMR (500 MHz, CDCl3): δ 1.45 (9H, s), 1.40-1.85 (6H, m), 3.02-3.15 (2H, m), 3.60 (1H, dd, J 12, 4Hz), 3.85-4.00 (4H, m); m/z (ES+) 176 (M++1-100, 100%).
    • (iii) tert-Butyl 4-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate
  • tert-Butyl 4-(1,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate (from step (ii) above; 480mg) was dissolved in dichloromethane and p-toluenesulfonyl chloride was added followed by triethylamine (0.49mL) and the mixture was stirred for 12h. An additional aliquot of triethylamine was added (0.49mL) and the mixture stirred for 48h. This mixture was concentrated in vacuo. The crude product was purified by chromatography on silica using 50-95% ethyl acetate in iso-hexane as eluant to afford the product (300mg).
    1H NMR (500 MHz, CDCl3): δ 1.45 (9H, s), 1.48-1.67 (2H, br m), 1.95 (1H, mc), 2.32 (1H, mc), 3.18 (2H, mc), 3.72-3.83 (1H, br m), 3.85 (2H, mc), 3.99 (2H, mc);
    m/z (ES+) 158 (M++1-100, 100%).
    • (iv) 4-Hydroxy-1-oxa-8-azaspiro[4.5]decane trifluoroacetate
  • tert-Butyl 4-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (iii) above; 300mg) was dissolved in dichloromethane and trifluoroacetic acid (2mL) was added. The solution was stirred for 2h and was concentrated in vacuo to afford the product as a colorless oil.
    1H NMR (500 MHz, CDCl3): δ 1.61-1.66 (1H, m), 1.89-2.06 (3H, m), 2.27-2.31 (2H, m), 3.20-3.33 (3H, m), 3.35-3.42 (1H, m), 3.85 (1H, mc), 3.99 (1H, q, J 8.5Hz), 4.07 (1H, dd, J 6.5, 4.0Hz); m/z (ES+) 158 (M++1, 100%).
    • DESCRIPTION 21 4-Hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane (i) Benzyl 4-(acetyloxy)-3,3-dimethyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate
  • A solution of 1-benzyl 4-ethyl piperidine-1,4-dicarboxylate (2.35g) was dissolved in tetrahydrofuran (30mL) and was cooled to -78°C. Lithium bis(trimethylsilyl)amide (9mL, 1M) was added dropwise under nitrogen and the solution was stirred for 30min at -20°C. The solution was re-cooled to -78°C and 1,1-dimethyl-2-oxoethyl acetate (1.17g) in tetrahydrofuran (5mL) was added and the mixture was stirred for 30min. The mixture was quenched (NaHCO3, 30mL) and the mixture was extracted with ethyl acetate (2 x 50 mL). The extracts were combined, washed with brine, dried (MgSO4) and were concentrated in vacuo. The crude product was purified by chromatography on silica using 25-75% ethyl acetate in iso-hexane as eluant to afford the product (1.4g).
    m/z (ES+) 376 (M++1, 100%).
    • (ii) Benzyl 4-(1,2-dihydroxy-2-methylpropyl)-4-(hydroxymethyl)piperidine-1-carboxylate
  • Benzyl 4-(acetyloxy)-3,3-dimethyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (i) above; 1.4g) was dissolved in tetrahydrofuran and lithium borohydride (81mg) was added. The mixture was heated under reflux for 2h, cooled and quenched carefully with water and HCl (30mL, 5N). The mixture was extracted with ethyl acetate and dried (MgSO4), and concentrated in vacuo. The crude product was purified by chromatography on silica using 2-5% methanol in dichloromethane as eluant to afford the product (340mg).
    m/z (ES+) 338 (M++1, 80%) 320 (M++1-18, 100%).
    • (iii) Benzyl 4-hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate
  • Benzyl 4-(1,2-dihydroxy-2-methylpropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (from step (iii) above; 340mg) was dissolved in dichloromethane and p-toluenesulfonyl chloride (190mg) was added, followed by triethylamine (0.14mL). This mixture was stirred for 2 h and a second aliquot of triethylamine was added and the mixture was stirred for 12h. The mixture was concentrated in vacuo. The crude product was purified by chromatography on silica using 50-100% ethyl acetate in iso-hexane as eluant to afford the product (190mg).
    1H NMR (500 MHz, CDCl3): δ 1.18 (3H, s), 1.29 (3H, s), 1.46-1.59 (2H, m), 1.62-1.78 (2H, m), 3.00-3.13 (2H, m), 3.55 (1H, d, J 9.3Hz), 3.73 (1H, d, J 9.3Hz), 3.84-3.95 (2H, m), 5.12 (2H, s), 7.29-7.36 (5H, m); m/z (ES+) 320 (M++1, 100%).
    • (iv) 4-Hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane
  • Benzyl 4-hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (iii) above; 180mg) was dissolved in methanol and palladium on carbon (5%) was added. The mixture was hydrogenated at atmospheric pressure for 30 min. The catalyst was removed by filtration through Hyflo™ and the solvent was evaporated in vacuo to afford the product as a white solid.
    1H NMR (500 MHz, CDCl3): δ 1.13 (3H, s), 1.24 (3H, s), 1.45-1.50 (2H, m), 1.67-1.79 (2H, m), 2.64-2.71 (2H, m), 2.89-3.00 (2H, m), 3.47 (1H, s), 3.59 (1H, d, J 9.2Hz), 3.72 (1H, d, J9.2Hz); m/z (ES+) 186 (M++1, 100%).
    • DESCRIPTION 22 1-Oxa-8-aza[4.5]decan-3-ol (i) tert-Butyl 4-hydroxy-4-{3-[(trimethylsilyl)oxy]prop-1-yn-1-yl}piperidine-1-carboxylate
  • Ethyl magnesium bromide in tetrahydrofuran (55mL, 1M, 55mmol) was slowly added to a solution of trimethyl(prop-2-yn-1-yloxy)silane in tetrahydrofuran (40mL) maintaining a temperature of 0°C. After the complete addition the mixture was stirred at ambient temperature for 45 min before a solution of tert-butyl piperidin-4-one-1-carboxylate (10g, 50mmol) in tetrahydrofuran (40mL) was slowly added at 0°C. Subsequently the reaction mixture was stirred for 18h at ambient temperature. Then saturated ammonium chloride solution was added and the mixture was stirred vigorously until the dissolution of all solids. The phases were separated and the aqueous was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 16.42g of desired product (96 %) as a yellow oil.
    1H NMR (360 MHz, CDCl3): δ 4.16 (2H, s), 3.55 (2H, br m), 3.12 (2H, ddd, J 3.8, 9.3, 12.8Hz), 1.74-1.66 (2H, m), 1.53 (2H, ddd, J 4, 9, 12.8Hz), 1.28 (9H, s).
    • (ii) tert-Butyl 4-hydroxy-4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylate
  • tert-Butyl 4-hydroxy-4-{3-[(trimethylsilyl)oxy]prop-1-yn1-1-yl}piperidine-1-carboxylate (crude from step (i); 16.42g, ca. 50mmol) was stirred with tetrabutylammonium fluoride (90mmol) in tetrahydrofuran (170mL) at ambient temperature for 18h. Then the solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was separated and the aqueous was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product as an amber oil, which was purified by flash chromatography on silica gel, eluting with 5 % methanol in dichloromethane to yield the desired diol (10.87g, 85 %).
    1H NMR (360 MHz, CDCl3): δ 4.32 (2H, br s), 3.80-3.69 (2H, br m), 3.28 (2H, ddd, J 3.5, 9.2, 13.2Hz), 1.92-1.84 (2H, br m), 1.74 (2H, ddd, J 3.8, 8.9, 12.7Hz), 1.46 (9H, s).
    • (iii) tert-Butyl 4-hydroxy-4-(3-hydroxyprop-1-ene-1-yl}piperidine-1-carboxylate
  • tert-Butyl 4-hydroxy-4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylate (from step (ii); 10g, 39.2mmol) was stirred at ambient temperature with Lindlar's catalyst (5 % Pd on CaCO3 poisoned with Pb) (4.15g, 2mmol of Pd) in ethanol under hydrogen (p ≥ 1 atm) for 18h. Then the catalyst was filtered off and the filtrate concentrated under reduced pressure to give 10.2g of the desired cis-olefin as a pale yellow oil.
    1H NMR (360 MHz, CDCl3): δ 5.66-5.56 (2H, m), 4.33 (2H, d, J 5.2Hz), 3.77-3.67 (2H, m), 3.30-3.24 (2H, m), 1.73-1.63 (4H, m), 1.46 (9H, s).
    • (iv) tert-Butyl 1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate
  • To a solution of tert-butyl 4-hydroxy-4-(3-hydroxyprop-1-ene-1-yl)piperidine-1-carboxylate (from step (iii); 8.79g, 34.2mmol) and triethylamine (7.6g, 75.2mmol) in tetrahydrofuran (170mL), methanesulfonyl chloride (4.31, 37.6mmol) was slowly added so that the internal temperature stayed between -10 and -5°C. After the complete addition the temperature was allowed to rise to 12°C and was kept at that temperature until all starting diol was turned over (monitored by TLC (silica gel, 1: 1 hexane/ethyl acetate)). Subsequently the reaction mixture was stirred for 2 days to complete the cyclisation before it was concentrated under reduced pressure. The residue was treated with water under icecooling, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 9g of crude product as yellow oil. This was purified by flash chromatography on silica gel, eluting with a gradient solvent system of 10-20 % ethyl acetate in hexane to give 5.79g of the desired spirocyclic product (64 %).
    1H NMR (360 MHz, CDCl3): δ 5.88 (1H, ddd, J 1.7, 1.7, 6.1Hz), 5.74 (1H, ddd, J 2.2, 2.2, 6.3Hz), 4.64 (2H, dd, J 1.6, 2.2Hz), 3.79-3.69 (2H, br m), 3.28 (2H, ddd, J 3.64, 10.5, 13.8Hz), 1.68-1.54 (4H, m), 1.46 (9H, s).
    • (v) tert-Butyl 1-oxa-8-aza[4.5]decan-3-ol-8-carboxylate
  • Borane-tetrahydrofuran-complex solution in tetrahydrofuran (16.7mL, 1M. 16.7mmol) was added to a solution of tert-butyl 1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate (from step (iv) above; 2g, 8.37mmol) in tetrahydrofuran (25mL) at 0°C. After 1h at room temperature, a mixture of 35 % w/w hydrogen peroxide solution (6mL, ca. 67mmol) and 4 M sodium hydroxide solution (17m) was slowly added at 0°C. Then the reaction mixture was stirred at room temperature for 18h before it was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium sulfite solution, then brine and finally dried over magnesium sulfate, filtered and concentrated to give the crude mixture of products as a colourless oil. The mixture was separated by flash chromatography on silica gel, eluting with a gradient solvent system of 50-100 % ethyl acetate in hexane, then 1-2 % methanol in ethyl acetate to furnish 1.03g of the title compound (48 %).
    1H NMR (360 MHz, CDCl3): δ 4.51-4.49 (1H, m), 3.92 (1H, dd, J 4.4, 10.1Hz), 3.84-3.79 (1H, m), 3.59 (1H, br s), 3.38-3.30 (1H, m) 1.96 (1H, dd, J 6.3, 13.6Hz), 1.85-1.79 (2H, m), 1.73-1.63 (2H, m), 1.58-1.50 (2H, m), 1.45 (9H, s).
    • (vi) 1-Oxa-8-aza[4.5]decan-3-ol trifluoroacetate
  • tert-Butyl 1-oxa-8-aza[4.5]decan-3-ol-8-carboxylate (from step (v) above; 1g, 3.89mmol) was stirred in a 1:1 v/v mixture of trifluoroacetic acid and dichloromethane (8mL) at ambient temperature for 0.5h. The reaction mixture was concentrated in vacuo to give 1.55g of a pale amber oil.
    1H NMR (360 MHz, CDCl3): δ 4.58-4.61 (1H, m), 3.87-4.02 (2H, m), 3.37-3.47 (2H, m), 2.26-1.75 (6H, m); m/z (ES+) 158.
    • EXAMPLE 1 (4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-yl] methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol
  • (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4R)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-yl ester (Description 14; 130mg, 0.15mmol) was dissolved in dichloromethane (3ml) and the solution was cooled to -78°C under nitrogen. A solution of diisobutylaluminium hydride (0.9ml, 1M in toluene) was added dropwise and the solution was stirred for 30min. Methanol (0.1ml) was added dropwise and the resulting quenched solution was poured carefully onto sodium hydroxide (10ml, 4M). This was stirred for 30min. The organic extracts were pooled, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel using 1-5% methanol in dichloromethane as eluant. This afforded the product as a white foam (96mg, 93%).
    This was further purified by recrystallisation of the HCl salt from ether-dichloromethane to give the product as white crystals (86mg).
    1H NMR (500MHz, CDCl3): δ 7.69 (1H, s), 7.23 (1H, dd, J 2.1, 6.5Hz), 7.21 (2H, s), 6.98 (1H, t, J 8.3Hz), 6.89-6.92 (1H, m), 4.95(1H, q, J 6.5Hz), 4.10-4.14 (2H, m), 4.03 (1H, dd, J 4.6, 10.0Hz), 3.90 (1H, dd, J 1.7, 4.4Hz), 3.65 (1H, dd, J 2.2, 10.0Hz), 3.59 (1H, d, J 8.5Hz), 3.54 (1H, d, J 8.5Hz), 3.51 (1H, dd, J 12.1, 2.0Hz), 2.39-2.37 (1H, m), 2.37 (1H, dd, J 8.3, 11.0Hz), 2.28-2.20 (1H, m), 2.12-1.84 (6H, m), 1.73 -1.68 (1H, m), 1.49-1.43 (2H, m), 1.39 (3H, d, J 6.6Hz); m/z (ES+) 684 (M++1, 95%), 686 (M++1, 100%).
    • EXAMPLE 2 (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol
  • Triethylamine (140µL, 1.0mmol) was added to a suspension of 2-oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride (Description 8; 0.1g, 0.54mmol) in 1,2-dichloroethane (2ml). After 10 minutes, (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-carbaldehyde (see Example 43 in WO 00/56727 ; 0.24g, 0.54mmol) was added as a solution in 1,2-dichloroethane (3ml). The mixture was stirred at room temperature for 30 minutes then sodium triacetoxyborohydride (0.2g, 0.94mmol) was added. The reaction was stirred at room temperature overnight. The mixture was partitioned between dichloromethane and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to give the title compound (72mg, 23%).
    1H NMR (400 MHz, CDCl3): δ 7.58 (1H, s), 7.16-7.15 (3H, m), 7.09 (2H, s), 6.95-6.92 (2H, m), 4.87 (1H, q, J 6.6Hz), 4.12 (1H, d, J 8.3Hz), 4.07 (1H, dd, J 3.5, 11.7Hz), 3.96-3.93 (1H, m), 3.83-3.81 (1H, m), 3.59-3.43 (4H, m), 2.41-2.38 (1H, m), 2.34-2.29 (1H, m), 2.21-2.15 (1H, m), 2.05-1.85 (5H, m), 1.74-1.66 (2H, m), 1.45-1.34 (4H, m), 1.29 (3H, d, J 6.6Hz).
    • EXAMPLE 3 (4S)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl] methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol
  • A solution of (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4RS)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-yl ester (Description 12; 138mg, 0.175mmol) in dichloromethane (5ml) was cooled to -78°C and diisobutylaluminium hydride (1.5M in toluene, 0.5ml, 0.75mmol) added. The reaction was stirred for 30 minutes then quenched by the addition of 2M aqueous sodium hydroxide solution. The mixture was allowed to warm to room temperature then dried over Na2SO4 and filtered through Celite™. The filtrate was concentrated in vacuo and the residue purified by preparative thin layer chromatography, eluting with 7% methanol/dichloromethane to give the title compound (27mg, 26%).
    1H NMR(360 MHz, CDCl3): δ 7.67 (1H, s), 7.17 (2H, s), 7.00-6.92 (4H, m), 4.95 (1H, q, J 6.5Hz), 4.15-4.11 (2H, m), 4.04-4.00 (1H, m), 3.90-3.89 (1H, m), 3.67-3.60 (2H, m), 3.54-3.48 (2H, m), 2.52-2.42 (1H, m), 2.41-2.36 (1H, m), 2.34-2.14 (2H, m), 2.10-1.87 (4H, m), 1.86-1.76 (1H, m), 1.75-1.67 (1H, m), 1.55-1.40 (4H, m), 1.36 (3H, d, J 6.5Hz); m/z (ES+) 606 (M+H)+.
    • EXAMPLE 4 (4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol
  • The title compound was prepared from (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4R)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-yl ester (Description 13) according to the method of Example 3.
    1HNMR (360 MHz, CDCl3): δ 7.67 (1H, s), 7.17 (2H, s), 7.03-6.89 (4H, m), 4.95 (1H, q, J 6.6Hz), 4.13 (2H, m), 4.02 (1H, dd, J 4.7, 9.8Hz), 3.90 (1H, m), 3.65 (1H, dd, J 2.0, 10.2Hz), 3.59 (1H, d, J 8.2Hz), 3.53 (1H, dd, J 8.6Hz), 3.50 (1H, dd, J 1.6, 12.1 Hz), 2.57-1.52 (11H, m), 1.60-1.40 (4H, m), 1.36 (3H, d, J 6.5Hz); m/z (ES+) 606 (M+H)+.
    • EXAMPLE 5 (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol
  • A mixture of methanesulfonic acid [(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methyl ester (Description 16; 0.275g, 0.49mmol), 2-oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride (Description 8; 0.1g, 0.37mmol), potassium carbonate (237g, 1.7mmol) and acetonitrile (3ml) was stirred at 55°C overnight and then at 65°C for 18 hours. The mixture was treated with water and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by preparative TLC (dichloromethane: methanol) to give the title compound.
    m/z (ES+) 624 (M+H)+.
    • EXAMPLE 6 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane
  • A mixture of 2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde (Description 11; 0.15g, 0.32mmol), 2-oxa-8-azaspiro[4.5]decane hydrochloride (0.85g, 0.48mmol), triethylamine (50µL, 0.49mmol), sodium triacetoxyborohydride (0.136g, 0.64mmol) and dichloroethane (3ml) was stirred at room temperature for 2 hours. The mixture was treated with sodium bicarbonate and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on alumina (grade III) using ethyl acetate in hexane (10-50%) to give the title compound.
    1NMR (360 MHz, CDCl3): δ 1.36 (3H, d, J 6.6Hz), 1.38-1.55 (5H, m), 1.61 (2H, t, J 7.1Hz), 1.82-2.05 (6H, m), 2.18-2.31 (2H, m), 2.37 (1H, dd, J 10.5, 8.4Hz), 3.43 (2H, s), 3.51 (1H, br t), 3.77 (2H, t, J 7.1Hz), 4.10-4.14 (2H, m), 4.95 (1H, q, J 6.6Hz), 6.91-7.01 (4H, m), 7.17 (2H, s), 7.67 (1H, s); m/z (ES+) 591 (M++H, 100%).
    • EXAMPLE 7 8-[(2R,3S,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane
  • A mixture of (2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde (see Example 43 in WO 00/56727 ) and 1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane (Bioorg. and Med. Chem. Lett. 2002, 12, 1759) was reacted and purified according to the procedure described in Example 6 to give the title compound. 1H NMR (360 MHz, CDCl3): δ 1.07 (3H, s), 1.08 (3H, s), 1.20-1.37 (3H, m), 1.46 (3H, d, J 6.6Hz), 1.50-1.64 (3H, m), 1.78-1.91 (3H, m), 2.0-2.15 (3H, m), 2.57-2.71 (3H, m), 2.97-3.02 (1H, m), 3.72-3.79 (3H, m), 4.04-4.10 (1H, m), 4.41 (1H, d, 3.2Hz), 4.95 (1H, q, J 6.6Hz), 7.24-7.26 (5H, m), 7.36 (2H, s), 7.67 (1H, s); m/z (ES+) 600 (M++H, 100%)
    • EXAMPLE 8 8-[(2R,3S,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)] methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane
  • A mixture of (2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde (see Example 43 in WO 00/56727 ) and 2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane (Description 18) was reacted and purified according to the procedure described in Example 6 to give the title compound.
    1H NMR (360 MHz, CDCl3): δ 1.20 (6H, s), 1.44 (3H, d, J 6.6Hz), 1.46-1.55 (4H, m), 1.60-1.71 (1H, m), 1.72-1.82 (4H, m), 1.82-1.95 (1H, m), 1.95-2.18 (3H, m), 2.25-2.38 (2H, m), 2.50-2.65 (3H, m), 3.73-3.75 (1H, m), 3.97-4.04 (1H, m), 4.41 (1H, d, 2.3Hz), 4.87 (1H, q, J 6.6Hz), 7.18 (2H, s) 7.18-7.32 (5H, m), 7.58 (1H, s); m/z (ES+) 600 (M++H, 100%)
    • EXAMPLE 9 8-[(2R,3S,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane
  • A mixture of (2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde (see Example 43 in WO 00/56727 ) and 1-oxa-8-aza-spiro[4.5]decane (Description 17) was reacted and purified according to the procedure described in Example 6 to give the title compound.
    1H NMR (360 MHz, CDCl3): δ 1.45 (3H, d, J 6.6Hz), 1.46-1.70 (7H, m), 1.86-2.32 (7H, m), 2.40-2.75 (4H, m), 3.73-3.78 (3H, m), 4.04-4.10 (1H, m), 4.41 (1H, d, 3.0Hz), 4.95 (1H, q, J 6.6Hz), 7.18-7.29 (5H, m) 7.35 (2H, s), 7.67 (1H, s); m/z (ES+) 572 (M++H, 100%).
    • EXAMPLE 10 8-[(2R,3S,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane
  • A mixture of (2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde (see Example 43 in WO 00/56727 ) and 2-oxa-8-aza-spiro[4.5]decane (Bioorg. and Med. Chem. Lett. 2002, 12, 1759) was reacted and purified according to the procedure described in Example 6 to give the title compound.
    1H NMR (360 MHz, CDCl3): δ 1.45 (3H, d, J 6.6Hz), 1.48-1.70 (5H, m), 1.66 (2H, t, J 7.1Hz), 1.86-1.98 (1H, m), 2.01-2.20 (4H, m), 2.36-2.48 (2H, m), 2.56 (1H, dd, J 11.9, 3.0Hz), 2.58-2.70 (1H, m), 3.48 (2H, s), 3.75 (1H, dd, J 11.1, 3.7Hz), 3.81 (2H, t, J 7.1Hz), 3.97-4.04 (1H, m), 4.42 (1H, d, J 3.0Hz), 4.87 (1H, q, J 6.6Hz), 7.18 (2H, s), 7.19-7.29 (5H, m), 7.59 (1H, s); m/z (ES+) 572 (M++H, 100%).
    • EXAMPLE 11 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane
  • A mixture of (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde (see Example 45 in WO 00/56727 ) and 2-oxa-8-aza-spiro[4.5]decane (Bioorg. and Med. Chem. Lett. 2002, 12, 1759) was reacted and purified according to the procedure described in Example 6 to give the title compound.
    1H NMR (360 MHz, CDCl3): δ 1.35 (3H, d, J 6.6Hz), 1.40-1.50 (3H, m), 1.60 (2H, t, J 7.1Hz), 1.85-2.05 (6H, m), 2.20-2.42 (3H, m), 3.42 (2H, s), 3.52 (1H, multiplet centre (mc)), 3.77 (2H, t, J 7.1 Hz), 4.10-4.16 (1H, m), 4.18 (1H, d, J 8.0Hz), 4.94 (1H, q, J 6.6Hz), 6.99-7.01 (2H, s), 7.16 (2H, s), 7.21-7.25 (3H, m), 7.65 (1H, s); m/z (ES+) 572 (M++H, 100%).
    • EXAMPLE 12 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane
  • A mixture of (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde (see Example 45 in WO 00/56727 ) and 2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane (Description 18) was reacted and purified according to the procedure described in Example 6 to give the title compound.
    1H NMR(360 MHz, CDCl3): δ 1.16 (6H, s), 1.35 (3H, d, J 6.6Hz), 1.38-1.61 (5H, m), 1.71 (4H, br s), 1.86-2.02 (5H, m), 2.15-2.22 (2H, m), 2.31-2.48 (2H, m), 3.50 (1H, br t), 4.08-4.15 (1H, m), 4.17 (1H, d, J 8.3Hz), 4.93 (1H, q, J6.6Hz), 6.98-7.00 (2H, m), 7.16 (2H, s) 7.20 (3H, br s), 7.65 (1H, s); m/z (ES+) 600 (M++H, 100%).
    • EXAMPLE 13 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane
  • A mixture of (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde (see Example 45 in WO 00/56727 ) and 1-oxa-8-aza-spiro[4.5]decane (Description 17) was reacted and purified according to the procedure described in Example 6 to give the title compound.
    1H NMR (360 MHz, CDCl3): δ 1.35 (3H, d, J 6.6Hz), 1.46-1.66 (8H, m), 1.84 (2H, qn), 1.90-2.32 (6H, m), 2.37 (2H, t, J 7.1Hz), 3.53 (1H, br t), 3.73 (2H, t, J 7.1Hz), 4.13 (1H, dd, J 11.7, 3.4Hz), 4.18 (1H, d, 8.2Hz), 4.94 (1H, q, J 6.6Hz), 6.96-7.01 (2H, m), 7.16 (2H, s), 7.21 (3H, br s), 7.65 (1H, s); m/z (ES+) 572 (M++H, 100%)
    • EXAMPLE 14 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane
  • A mixture of (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde (see Example 45 in WO 00/56727 ) and 1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane (Bioorg. and Med. Chem. Lett. 2002, 12, 1759) was reacted and purified according to the procedure described in Example 6 to give the title product.
    1H NMR (360 MHz, CDCl3): δ 1.03 (6H, s), 1.15-1.28 (2H, m), 1.35 (3H, d, J 6.6Hz), 1.38-1.49 (2H, m), 1.50-1.59 (3H, m), 1.74 (2H, t, J 7.1Hz), 1.86-2.05 (4H, m), 2.38 (1H, br t), 2.51-2.58 (1H, m), 2.61-2.68 (1H, m), 3.52 (1H, br t), 3.73 (2H, t, J 7.1Hz), 4.13-4.19 (2H, m), 4.93 (1H, q, J 6.6Hz), 6.98-7.01 (2H, m), 7.16 (2H, s) 7.22 (3H, br s), 7.65 (1H, s); m/z (ES+) 600 (M++H, 100%).
    • EXAMPLE 15 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one
  • Dess-Martin periodinane (0.6g, 1.4mmol) was added to a solution of (4S)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol (Example 3; 0.85g, 1.4mmol) in dichloromethane (20ml). The mixture was stirred at room temperature for 4 hours then quenched by addition of saturated sodium hydrogen carbonate. After 30 minutes the mixture was partitioned between water and dichloromethane. The organic extracts were dried and concentrated. The residue was chromatographed on silica gel eluting with 2% methanol / dichloromethane to give the title compound (510mg, 60%).
    1H NMR (400 MHz, CDCl3): δ 7.67 (1H, s), 7.17 (2H, s), 6.99-6.91 (4H, m), 4.96 (1H, q, J 6.5Hz), 4.15-4.10 (2H, m), 3.96-3.90 (4H, m), 3.50 (1H, dt, J 2, 12.1Hz), 2.64-2.62 (1H, m), 2.52-2.49 (1H, m), 2.38 (1H, dd, J 8.4, 10.9Hz), 2.02-1.87 (5H, m), 1.76-1.66 (3H, m), 1.45-1.39 (3H, m), 1.37 (3H, d, J 6.6Hz).
    • EXAMPLE 16 (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl] methyl-2-oxa-4-methyl-8-aza-spiro[4.5]decan-4-ol
  • Methyl magnesium chloride (3.0M solution in tetrahydrofuran, 90µl) was added to a solution of 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one (Example 15; 100mg, 0.16mmol) stirring in tetrahydrofuran (2ml) at room temperature. After 2 hours the reaction was quenched by addition of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and water. The organic extracts were separated, dried and concentrated. The residue was chromatographed on silica gel eluting with dichloromethane/ methanol/ ammonia mixtures to give the title compound (66mg, 65%).
    1H NMR(400 MHz, CDCl3): δ 7.67 (1H, s), 7.17 (2H, s), 7.03-6.89 (4H, m), 4.95 (1H, q, J 6.6Hz), 4.13 (2H, m), 3.82 (1H, dd, J 5.9, 8.5Hz), 3.68-3.61 (3H, m), 3.54-3.51 (1H, m), 2.69-2.53 (2H, m), 2.39 (1H, td, J 2.9, 10.9Hz), 2.01-1.88 (5H, m), 1.62-1.41 (5H, m), 1.37 (3H, d, J 6.6Hz), 1.36-1.35 (1H, m), 1.15 (3H, s); m/z (ES+) 620 (M+H)+.
    • EXAMPLE 17 (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxyl-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-4-ethynyl-8-aza-spiro[4.5]decan-4-ol
  • Ethynyl magnesium bromide (0.5M solution in tetrahydrofuran, 0.5mL) was added to a solution of 8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one (Example 15) (100mg, 0.16mmol) stirring in tetrahydrofuran (2ml) at room temp. After 2 hours the reaction was quenched by addition of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and water. The organic extracts were separated, dried and concentrated. The residue was purified by chromatography on silica gel eluting with dichloromethane/ methanol/ ammonia mixtures to give the title compound (51mg, 49%). 1H NMR(400 MHz, CDCl3): δ 7.67 (1H, s), 7.26 (2H, s), 7.17-6.90 (4H, m), 4.95 (1H, q, J 6.6Hz), 4.15-4.10 (2H, m), 3.97-3.95 (1H, m), 3.90-3.84 (2H, m), 3.62-3.48 (2H, m), 2.69-2.57 (3H, m), 2.45 -2.36 (1H, m), 2.08-1.39 (11H, m), 1.37 (3H, d, J 6.6Hz); m/z (ES+) 630 (M+H)+.
    • EXAMPLE 18 (8S)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-phenyl)-tetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol
  • (2R,3R,4R)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-phenyltetrahydro-2H-pyran-4-carbaldehyde ( WO 00/56727 ) (760mg, 1.7mmol) and 6-oxa-2-azaspiro[3.4]octan-8-ol (Description 19) (214mg, 1.7mmol) were dissolved in 1,2-dichloroethane (20mL) and sodium triacetoxyborohydride (636mg, 3mmol) was added. The suspension formed was stirred at ambient temperature for 16hrs then quenched with 1N sodium hydroxide solution (50mL). The biphasic mixture formed was extracted with dichloromethane (2x50mL), and the extracts were dried (MgSO4) then concentrated to give a gum. The residue was purified by silica chromatography to give a mixture of the two diastereomers, which could be separated by chiral HPLC (Cyclobond II, 7.5% EtOH/hexane) to give isomer A (for isomer B, see Example 19):
    Isomer A: 1H NMR (400 MHz, CDCl3): δ 7.65 (1H, s), 7.24-7.21 (3H, m), 7.15 (2H, s), 7.03-6.99 (2H, m), 4.93 (1H, q, J 6.6Hz), 4.21 (1H, dd, J 2.9, 4.6Hz), 4.17 (1H, d, J 8.4Hz), 4.12 (1H, ddd, J 1.7, 4.6, 11.7Hz) 3.84 (1H, dd, J 4.6, 9.9Hz), 3.76 (2H, s), 3.62 (1H, dd, J 2.8, 9.0Hz), 3.50 (1H, dt, J 2.4, 12.3Hz), 3.37 (1H, d, J 7.4Hz), 3.03 (1H, d, J 6.9Hz), 2.80 (2H, dd, J 7.4, 14.8Hz), 2.41 (1H, dd J 8.0, 11.3Hz), 2.16 (1H, dd, J 9.5, 12.3Hz), 2.07 (1H, dd, J 3.3, 11.8Hz) 1.85-1.75 (2H, m), 1.63 (1H, br m), 1.52-1.41 (1H, m), 1.35 (3H, d, J 6.6Hz); m/z (ES+) 560 (M+H).
    • EXAMPLE 19 (8R)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol
  • This product was the second peak to elute from the prep HPLC run described in Example 18.
    Isomer B: 1H NMR (360 MHz, CDCl3): δ 7.65 (1H, s), 7.27-7.12 (5H, m), 7.01-6.99 (2H, m), 4.93 (1H, q, J 6.6Hz), 4.23 (1H, dd, J 3.2, 5.3Hz), 4.17 (1H, dd, J 9.3Hz), 4.12 (1H, ddd, J 2.0, 7.3, 11.8Hz), 3.84 (1H, dd, J 4.6, 9.8Hz), 3.75 (2H, s), 3.61 (1H, dd, J 3.1, 9.8Hz), 3.50 (1H, dt, J 2.4, 12.3Hz), 3.42 (1H, d, J 7.3Hz), 3.04 (1H, d, J 6.8Hz), 2.87 (1H, d, J 6.8Hz), 2.72 (1H, d, J 6.8Hz), 2.41 (1H, dd, J 8.5, 11 Hz), 2.17 (1H, dd, J 9.2, 12.0Hz), 2.07 (1H, dd, J 3.6, 12.6Hz), 1.86-1.76 (3H, m), 1.52-1.41 (1H, m), 1.35 (3H, d, J 6.6Hz); m/z (ES+) 560 (M+H).
    • EXAMPLE 20 (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran4-yl]methyl-1-oxa-8-azaspiro[4.5]decan4-ol
  • This product was prepared according to the procedure described in Example 2 using (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-carbaldehyde ( WO 0056727 ) and 4-hydroxy-1-oxa-8-azaspiro[4.5]decane (Description 20).
    1H NMR (500 MHz, CDCl3): δ 1.35 (3H, d, J 6.6Hz), 1.38-1.55 (2H, m), 1.6-1.98 (4H, m), 2.00-2.25 (4H, m), 2.38 (1H, dd, J 11.2, 8.4Hz), 2.39-2.7 (2H, m), 3.53 (1H, t, J 12.0Hz), 3.72-3.76 (1H, m), 3.89 (1H, multiplet centre (mc)), 4.13 (1H, dd, J 11.8, 3.4Hz), 4.20 (1H, d, J 8.3Hz), 4.94 (1H, q, J 6.5Hz), 6.99-7.00 (2H, m), 7.16 (2H, s), 7.21-7.22 (3H, m), 7.65 (1H, s); m/z (ES+) 588 (M++1, 100%).
    • EXAMPLE 21 (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-4-ol
  • This product was prepared according to the procedure described in Example 6 using (2R,3R,4R)-2-[(1R)-1-(3, 5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde (Description 11) and 4-hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane (Description 21).
    1H NMR (400 MHz, MeOD): δ 1.12 (3H, s), 1.24 (3H, s), 1.36 (3H, d, J 6.6Hz), 1.39-1.44 (2H, m), 1.56-1.78 (4H, m), 1.82-2.06 (4H, m), 2.37 (1H, t, J 9.1Hz), 2.39-2.56 (2H, m), 3.44 (1H, s), 3.45-3.58 (3H, m), 4.10-4.14 (2H, m), 4.95 (1H, q, J 6.6Hz), 6.91-6.99 (4H, m), 7.17 (1H, s), 7.67 (1H, s); m/z (ES+) 634 (M++1, 100%).
    • EXAMPLE 22 (4R*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol
  • This compound was prepared from the reaction of the compounds of Description 11 and 20 following the procedure described in Example 6. The product was purified by chromatography on silica to give a mixture of two diastereomers, which were separated by chiral HPLC (Cyclobond II, 7.5% EtOH/hexane) to give isomer A:
    1H NMR (500MHz, CDCl3): δ 7.67 (1H, s), 7.17 (2H, s), 6.98-6.90 (4H, m), 4.95 (1H, q, J 6.4Hz), 4.12 (2H, dd, J 2.1, 8.3Hz), 3.93-3.89 (2H, m), 3.78-3.74 (1H, m), 3.52 (1H, dd, J 12.1, 12.1Hz), 2.38 (2H, t, J 8.7Hz), 2.29-2.19 (3H, m), 2.01 (2H, m), 1.93 (2H, m), 1.85 (1H, m), 1.71 (1H, m), 1.41 (3H, s), 1.36 (3H, d, J 6.6Hz); m/z (ES+) 606.
    • EXAMPLE 23 (4S*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol
  • This compound was prepared from the reaction of the compounds of Description 11 and 20 following the procedure described in Example 6. The product was purified by chromatography on silica to give a mixture of two isomers, which were separated by chiral HPLC (Chiralpak AD, 2% EtOH in hexane) to give isomer A (see Example 22) and isomer B:
    1H NMR (500MHz, CDCl3): δ 7.67 (1H, s), 7.17 (2H, s), 6.98-6.90 (4H, m), 4.97-4.93 (1H, q, J 6.6Hz), 4.12 (2H, dd, J 2.6, 8.4Hz), 3.93-3.87 (2H, m), 3.79-3.73 (1H, m), 3.51 (1H, dd, J 10, 10Hz), 2.47 (1H, m), 2.38 (1H, t, J 9.6Hz), 2.26-2.19 (3H, m), 2.03-1.93 (5H, m), 1.88-1.82 (1H, m), 1.40-1.34 (6H, m); m/z (ES+) 606.
    • EXAMPLE 24 (4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane
  • To a solution of (4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl]methyl-2-oxa-8-azaspiro[4.5]decan-4-ol (Example 2) (100 mg, 0.17mmol) in anhydrous DMF (1mL) was added a 60 % dispersion of sodium hydride in mineral oil (40mg) under ice cooling. After 15 min of stirring at 0°C methyl iodide (31mg) was added and the mixture was stirred at r.t. for 18h, before it was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product as colourless oil, which was then purified by flash chromatography on silica using 3-5 % methanol in dichloromethane as eluant. The desired product was obtained as colourless viscous oil (76 %).
    1H NMR(360 MHz, CDCl3): δ 7.65 (1H, s), 7.22 (3H, m), 7.16 (2H, s), 7.01 (2H, m), 4.94 (1H, q, J 6.6Hz), 4.18 (1H, d, J 8.4Hz), 4.13 (1H, dd, J 3.3, 15Hz), 3.90 (1H, dd, J 4.4, 9.8Hz), 3.77 (1H, dd, J 2.0, 9.9Hz), 3.56-3.48 (3H, m), 3.38-3.34 (1H, m), 3.25 (3H, s), 2.41-2.35 (2H, m), 2.19-2.06 (2H, m), 2.06-1.87 (7H, m), 1.79-1.73 (1H, m), 1.47-1.39 (4H, m), 1.35 (3H, d, J 6.6Hz); m/z (ES+) 602.
    • EXAMPLE 25 (4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)tetrahydro-2-H-pyran-4-yl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane
  • This compound was prepared from the compound of Example 4 following the procedure described in Example 24.
    1H NMR (360 MHz, CDCl3): δ 7.67 (1H, s), 7.17 (2H, s), 7.00-6.92 (4H, m), 4.95 (1H, q, J 6.6Hz), 4.16-4.09 (2H, m), 3.90 (1H, dd, J 4.4, 9.9Hz), 3.77 (1H, dd, J 2.1, 9.9Hz), 3.56-3.48 (3H, m), 3.37 (1H, dd, J 2.1, 4.3Hz), 3.26 (3H, s), 2.41-2.33 (2H, m), 2.16-2.07 (2H, m), 2.02-1.84 (5H, m), 1.79-1.71 (1H, m), 1.49-1.39 (2H, m), 1.36 (3H, d, J 6.6Hz); m/z (ES+) 620, 362.
    • EXAMPLE 26 8-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-ol
  • To a solution of (2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-carbaldehyde ( WO 00/56727 ) (0.97g, 2.7 1 mmol) and triethylamine (0.72mL, 5.17mmol) in 1,2-dichloroethane (15mL) was added 1-oxa-8-aza[4.5]decan-3-ol trifluoroacetate (Description 22) (775 mg), followed by sodium triacetoxyborohydride (630 mg, 3mmol). The reaction mixture was stirred for 2h at room temperature, then treated with dilute sodium hydroxide solution and extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude product as a light brown oil. Flash chromatography on a column of silica gel with a gradient solvent system of 5-10 % methanol in dichloromethane afforded the title compound as a mixture of epimers (53 %, 0.85g).
    1H NMR (360 MHz, CDCl3): δ 7.66 (1H, s), 7.22 (3H, s), 7.16 (2H, s), 7.00 (2H, m), 4.94 (1H, q, J 6.6Hz), 4.43 (1 H, br s), 4.20 (1H, d, J 8.2Hz), 4.13 (1H, dd, J 3.3, 11.9Hz), 3.82 (1H, dd, J 4.2, 9.9Hz), 3.72 (1H, d, J 10.1 Hz), 3.54 (1H, dd, J 12, 12Hz), 2.59-1.41 (ca. 20H, methylene envelope), 1.24 (3H, d, J 6.6Hz); m/z (ES+) 588.
    • EXAMPLE 27 8-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-one
  • This compound was prepared from the compound of Example 26 following the procedure described in Example 15.
    1H NMR(360 MHz, CDCl3): δ 7.65 (1H, s), 7.23-7.19 (3H, m), 7.17 (2H, s), 7.09-6.97 (2H, m), 4.94 (1H, q, J 6.5Hz), 4.18 (1H, d, J 8.3Hz), 4.13 (1H, dd, J 4.2, 11.7Hz), 3.92 (2H, s), 3.53 (1H, t, J 11.1Hz), 2.49-2.42 (1H, m), 2.39 (1H, dd, J 8.4, 10.8Hz), 2.31-2.17 (2H, m), 2.05 (2H, dd, J 10.2, 12.6Hz), 2.00-1.93 (3H, m), 1.76-1.68 (2H, m), 1.67-1.58 (2H, m), 1.48-1.38 (1H, m), 1.36 (3H, d, J 6.6Hz); m/z (ES+) 586.

Claims (9)

  1. A compound of the formula (Ia):
    Figure imgb0016
     wherein
    R1 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb each independently represent hydrogen or C1-4alkyl;
    R2 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
    R3 is hydrogen, halogen or fluoroC1-6alkyl;
    R4 is hydrogen, halogen, C1-4alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, hydroxy, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb are as previously defined;
    R5 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
    R6 represents hydrogen or a C1-4alkyl group optionally substituted by a hydroxy group;
    R7 represents hydrogen, C1-6alkyl, fluoroC1-6alkyl, hydroxy, C1-6alkoxy or hydroxyC1-6alkyl;
    R8 and R9 each independently represent hydrogen, halogen, C1-6alkyl, CH2ORc, oxo, CO2Ra or CONRaRb where Ra and Rb are as previously defined and Rc represents hydrogen, C1-6alkyl or phenyl;
    A represents an oxygen atom or a CH2 group;
    B represents an oxygen atom or a CH2 group, with the proviso that when A is an oxygen atom, B is a CH2 group, and when A is a CH2 group, B is an oxygen atom;
    n is 1 or 2;
    m is 1,2 or 3, with the proviso that the sum total of m + n is 2, 3 or 4;
    R10 is hydrogen, halogen, hydroxy, C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, C2-6alkenyl or C2-6alkynyl;
    R11 is hydrogen, halogen, hydroxy or C1-4alkyl;
    or R10 and R11 may together represent an oxo (=O) group, with the proviso that the oxo group is not adjacent to the oxygen atom represented by either A or B;
    wherein one or both of R10 and R11 may replace one or both hydrogen atoms in the CH2 group represented by A or B;
    or a pharmaceutically acceptable salt thereof.
  2. A compound as claimed in Claim 1 of the formula (Iaa)
    Figure imgb0017
     wherein
    A1 is fluorine or CF3;
    A2 is fluorine or CF3;
    A3 is hydrogen or fluorine;
    A4 is hydrogen, fluorine or bromine;
    A5 is methyl or hydroxymethyl; and
    A, B, R10 and R11 are as defined in Claim 1;
    or a pharmaceutically acceptable salt thereof.
  3. A compound as claimed in Claim 1 of the formula (Iab)
    Figure imgb0018
     wherein
    X represents CHOH or C=O;
    R1 is fluorine or trifluoromethyl;
    R2 is fluorine or trifluoromethyl;
    R3 is methyl or hydroxymethyl;
    R4 is hydrogen or fluorine; and
    R5 is hydrogen or fluorine;
    or a pharmaceutically acceptable salt thereof.
  4. A compound as claimed in Claim 3 of the formula (laba)
    Figure imgb0019
     wherein
    A1 is hydrogen or fluorine; and
    A2 is hydrogen or fluorine;
    or a pharmaceutically acceptable salt thereof.
  5. A compound as claimed in Claim 1, selected from:
    (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;
    (4S)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;
    (4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;
    (4RS)-8-[(2R,3R,4R)2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;
    8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)cthoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane;
    8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane;
    8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]mcthyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane;
    8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane;
    8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyrm-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane;
    8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyan-4-yl]mthyl-2-oxa-8-aza-spiro[4.5]decane;
    8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane;
    8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane;
    8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromcthyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane;
    8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one;
    (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-4-methyl-8-aza-spiro[4.5]decan-4-ol;
    (4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;
    (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-4-ethynyl-8-aza-spiro[4.5]decan-4-ol;
    (8S)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol;
    (8R)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenyl)tetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol;
    (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)thoxy]-3-phenyltetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;
    (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-4-ol;
    (4R*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;
    (4S*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;
    (4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane;
    (4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)tetrahydro-2H-pyran-4-yl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane;
    8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-ol;
    8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-one;
    or a pharmaceutically acceptable salt thereof.
  6. A compound as claimed in any one of Claims 1 to 5 for use in therapy.
  7. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 5, together with at least one pharmaceutically acceptable carrier or excipient.
  8. Use of a compound as claimed in any one of Claims 1 to 5 for the manufacture of a medicament for the treatment or prevention of physiological disorders associated with an excess of tachykinins.
  9. Use of a compound as claimed in any one of Claims 1 to 5 for the manufacture of a medicament for the treatment or prevention of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression or anxiety.
EP04717163A 2003-03-07 2004-03-04 Tetrahydropyran compounds as tachykinin antagonists Expired - Lifetime EP1603901B1 (en)

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GB0305279A GB0305279D0 (en) 2003-03-07 2003-03-07 Therapeutic agents
GB0305280A GB0305280D0 (en) 2003-03-07 2003-03-07 Therapeutic agents
GB0305282A GB0305282D0 (en) 2003-03-07 2003-03-07 Therapeutic agents
GB0305282 2003-03-07
GB0305283A GB0305283D0 (en) 2003-03-07 2003-03-07 Therapeutic agents
GB0305279 2003-03-07
GB0305283 2003-03-07
GB0305281 2003-03-07
GB0305280 2003-03-07
GB0305281A GB0305281D0 (en) 2003-03-07 2003-03-07 Therapeutic agents
GB0305822A GB0305822D0 (en) 2003-03-13 2003-03-13 Therapeutic agents
GB0305823 2003-03-13
GB0305823A GB0305823D0 (en) 2003-03-13 2003-03-13 Therapeutic agents
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PCT/GB2004/000918 WO2004078750A1 (en) 2003-03-07 2004-03-04 Tetrahydropyran compounds as tachykinin antagonists

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WO2004078750A1 (en) 2003-03-07 2004-09-16 Merck Sharp & Dohme Limited Tetrahydropyran compounds as tachykinin antagonists
JP5396918B2 (en) * 2008-03-14 2014-01-22 Ｊｓｒ株式会社 Carbonate group-containing compound and method for producing the same (co) polymer
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JO3517B1 (en) 2014-01-17 2020-07-05 Novartis Ag N-azaspirocycloalkane substituted n-heteroaryl compounds and compositions for inhibiting the activity of shp2
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CN112250611B (en) * 2020-11-27 2022-04-22 济南大学 Synthesis method of-2- (2, 5-difluorophenyl) pyrrolidine hydrochloride

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US7393858B2 (en) 2008-07-01
US20060172999A1 (en) 2006-08-03
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CA2517422A1 (en) 2004-09-16
WO2004078750A1 (en) 2004-09-16

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